Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive gastrointestinal cancers, with over 90% of cases harboring KRAS gene mutations. These mutations not only serve as key drivers of tumorigenesis but also reshape the tumor microenvironment (TME), creating a highly immunosuppressive “cold tumor” characterized by immune cell dysfunction, a dense fibrotic stroma, and a unique metabolic state. This immunosuppressive TME contributes to the widespread resistance of PDAC to immune therapies, such as immune checkpoint inhibitors (ICIs). This review systematically elucidates the mechanisms by which KRAS mutations shape the immune-suppressive TME, with a focus on the multimodal combination strategies developed to overcome this resistance. These strategies include combinations of ICIs with chemotherapy, radiotherapy, and targeted therapies (e.g., KRAS G12C/D inhibitors, PARP inhibitors, FAK inhibitors, MEK inhibitors), as well as explorations of novel immunotherapies like CAR-T cell therapy, oncolytic viruses, and T-cell agonists. Additionally, we discuss the potential of innovative localized drug delivery technologies, such as hydrogels, intelligent nanoparticle carriers, and oral spore systems, in enhancing intratumoral drug concentrations while reducing systemic toxicity. Despite the limited efficacy of monotherapy in immune treatment, increasing preclinical and clinical evidence suggests that well-designed combination strategies, by remodeling the TME through multiple targets, hold the promise of converting “cold tumors” into “hot tumors,” thereby restoring anti-tumor immune responses. Future breakthroughs in therapy will depend on the use of multi-omic biomarkers, including ctDNA, exosomes, and microbiomes, for precise patient stratification, guiding tailored immune combination therapies, and ultimately improving the survival outcomes of PDAC patients.
Keywords: Pancreatic ductal adenocarcinoma, KRAS mutation, Tumor immune microenvironment, Immunotherapy, Targeted therapy, Combination therapy
Introduction
PDAC is one of the most lethal malignancies of the digestive system, with a five-year overall survival rate of less than 10%, and an incidence rate that closely parallels its mortality rate [1] .This dismal clinical outcome is largely attributable to the insidious onset of the disease, the lack of effective methods for early diagnosis, its rapid progression, and the longstanding paucity of effective therapeutic options.
Within the complex molecular landscape of PDAC, KRAS mutations represent the predominant oncogenic driver, occurring in approximately 90% of cases [1, 2].For decades, KRAS was considered an “undruggable” target because its protein structure was thought to lack suitable binding pockets for conventional small-molecule inhibitors [3] .However, recent advances have led to the successful development of inhibitors targeting the KRAS G12C mutation, providing definitive proof of the druggability of KRAS and fundamentally reshaping our understanding of its biological functions. Beyond directly promoting autonomous tumor cell proliferation, oncogenic KRAS actively remodels the TME through downstream signaling pathways. Specifically, mutant KRAS facilitates the recruitment of immunosuppressive cell populations, including myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), induces functional exhaustion of effector T cells, and drives cancer-associated fibroblasts (CAFs) to establish a dense physical barrier within the tumor stroma [4–6].In parallel, KRAS-driven metabolic reprogramming results in nutrient deprivation and acidification of the microenvironment, collectively fostering a profoundly immunosuppressive, “cold” tumor phenotype [7–9].Consequently, with the exception of the rare subset of PDAC patients harboring high microsatellite instability (MSI-H) or deficient mismatch repair (dMMR) (< 1%), the vast majority of PDAC cases derive little to no clinical benefit from ICI monotherapy, including PD-1/PD-L1 or CTLA-4 blockade [10, 11].In contrast to KRAS-mutant PDAC, KRAS wild-type (KRAS-WT) PDAC exhibits significantly lower PD-L1 expression levels by immunohistochemistry (IHC), and harbors higher levels of classical biomarkers associated with immunotherapy response(such as dMMR/MSI and tumor mutational burden (TMB)). Furthermore, regarding the TME, KRAS-WT PDAC displays a lower degree of CAF infiltration than its mutant counterpart, resulting in a relatively attenuated physical barrier. Concurrently, it is characterized by elevated infiltration levels of immune effector cells, including CD4⁺ T cells, CD8⁺ T cells, and natural killer (NK) cells. Overall, KRAS-WT PDAC demonstrates a higher degree of immunological activity compared to KRAS-mutant PDAC [12]. In light of the central role of mutant KRAS in establishing an immunosuppressive TME, therapeutic strategies have shifted from single-agent ICI treatment toward multimodal and multitargeted combination approaches. These include combinations of immunotherapy with chemotherapy or radiotherapy, integration with targeted therapies—such as emerging KRAS G12C/G12D inhibitors, PARP inhibitors, and MEK inhibitors—as well as the exploration of novel immunotherapeutic modalities, including chimeric antigen receptor T (CAR-T) cell therapy, oncolytic viruses, and CD40 agonists [13–24].
This Review aims to systematically elucidate the key mechanisms by which KRAS mutations shape the immunosuppressive TME in PDAC and to comprehensively summarize recent advances in combination therapeutic strategies designed to overcome immune resistance. Furthermore, we discuss future perspectives on leveraging ctDNA, multi-omics profiling, and other emerging biomarkers to enable refined patient stratification and guide precision immunotherapy, ultimately providing new avenues to improve clinical outcomes for patients with KRAS-mutant PDAC [25, 26].
KRAS mutation subtypes and molecular characteristics in PDAC (Fig. 1)
Fig. 1.
Distribution of KRAS mutation subtypes in pooled multi-population pancreatic cancer data. The pie chart illustrates the relative frequencies of distinct KRAS mutation variants based on pooled multi-population data. The vast majority of these alterations occur at codon 12, with G12D (41%), G12V (32%), and G12R (16%) representing the most predominant subtypes. Minor variants account for the remainder, including Q61 mutations (7%) and other rare variants (4%). Mutation frequency distributions are primarily compiled from references [3, 26, 27]
More than 90% of PDAC cases harbor activating mutations in KRAS. These mutations abolish the intrinsic GTPase activity of the KRAS protein, locking it in a constitutively active, GTP-bound state and thereby driving persistent activation of multiple downstream signaling cascades, including the RAF–MEK–ERK and PI3K–AKT–mTOR pathways, which collectively promote malignant tumor progression [1, 2].KRAS mutations in PDAC exhibit pronounced subtype heterogeneity. Approximately 90% of mutations occur at codon 12, with G12D, G12V, and G12R representing the predominant variants, whereas the KRAS G12C mutation is relatively rare, accounting for only ~ 1–2% of cases [3, 27, 28].These distinct KRAS mutant subtypes are associated with divergent biological behaviors. G12D, the most prevalent subtype, provides sustained oncogenic signaling that drives early tumor initiation and progression [27, 28].In contrast, G12V exhibits a stronger capacity for downstream signal activation, highlighting the MEK/ERK pathway as a potential therapeutic target. Furthermore, compared with the G12D variant, G12V remodels the tumor microenvironment (TME) by promoting angiogenesis and reducing immunosuppressive factors. This facilitates enhanced cytotoxic T-cell infiltration and induces a more immunologically active TME, suggesting that patients with G12V mutations may preferentially benefit from immunotherapy [28, 29].Meanwhile, G12R alters signal transduction modes via unique charge-dependent effects, potentially conferring a distinct dependency on the MEK pathway [28]. Although KRAS G12C mutations are infrequent in PDAC, the successful development of allele-specific inhibitors targeting this variant represents a breakthrough in KRAS-directed therapy [3, 30]. Importantly, KRAS mutations rarely occur in isolation. They frequently co-occur with inactivating alterations in key tumor suppressor genes, including TP53, CDKN2A, and SMAD4, which act synergistically to drive PDAC progression and aggressiveness [3, 27].Notably, loss of SMAD4 can cooperate with TP53 deficiency to induce highly aggressive PDAC even in the absence of KRAS mutations [31].By contrast, the 5–10% of PDAC cases that are KRAS wild-type display a fundamentally distinct molecular landscape. These tumors typically lack the canonical co-mutation patterns observed in KRAS-mutant PDAC and instead are enriched for alternative oncogenic alterations, such as BRAF fusions and NRG1 rearrangements [32, 33].
KRAS mutations shape an immunosuppressive TME (Table 1)
Table 1.
Linking KRAS-Driven Immune Evasion Mechanisms to Rational Combination Strategies in Pancreatic Cancer
| Core Immune Evasion Mechanism | Specific Manifestations | Corresponding Combination Strategies | Rationale for Strategy |
|---|---|---|---|
| Immune Cell Dysfunction and Exhaustion1 |
Infiltration of immunosuppressive cells: MDSCs, Tregs, M2-polarized TAMs Upregulation of immune checkpoints: PD-L1/PD-1 Dysregulated cytokine secretion: IL-10, TGF-β, etc. |
1. ICI + T cell co-stimulatory agonists (e.g., CD40/CD137 agonists) 2. ICI + MEK inhibitor (e.g., trametinib) 3. CAR-T / cancer vaccines 4. ICI + radiotherapy / chemotherapy |
Given that KRAS signaling upregulates PD-L1 expression leading to T cell exhaustion, and that MDSCs/Tregs accumulate to suppress immune responses, the following strategies are warranted: ① co-stimulatory signal agonists to reverse T cell exhaustion; ② MEK inhibitors to block upstream signaling; ③ CAR-T or cancer vaccines to bypass endogenous T cell dysfunction; ④ radiotherapy/chemotherapy to induce immunogenic cell death and provide activated T cells for ICIs |
| Physical Barrier 2 |
Stromal hyperplasia: activated CAFs secrete dense extracellular matrix (ECM) components, including collagen and hyaluronan “Chemotactic misguidance”: specific CAF subsets secrete CXCL12, which traps T cells within the stroma, away from tumor cells |
1. ICI + matrix-targeting agents (e.g., FAK inhibitor / CXCR4 antagonist) 2. Oncolytic virus (e.g., VCN-01) 3. Local drug delivery systems |
Given that CAFs secrete dense ECM and CXCL12 to sequester T cells within the stromal compartment, the following strategies are warranted: ① FAK inhibitors to disrupt the stromal barrier and CXCR4 antagonists to relieve “chemotactic misguidance”; ② oncolytic viruses expressing hyaluronidase to directly degrade ECM; ③ local delivery systems to bypass the barrier and achieve high intratumoral drug accumulation |
| Metabolic Reprogramming3 |
“Warburg effect”: enhanced aerobic glycolysis, massive glucose consumption, and lactate production Lactate accumulation: leads to TME acidification |
1. ICI + KRAS/MEK pathway inhibitors 2. Specific local drug delivery systems |
Given that KRAS-driven Warburg effect results in glucose depletion and lactate accumulation, which suppress T cell function, the following strategies are warranted: ① targeting the KRAS/MEK pathway to reverse metabolic abnormalities; ② utilizing nanodelivery systems (e.g., M-MSN@DOX/Gox) to exacerbate tumor metabolic stress |
| Multi-Mechanism Synergistic Immune Evasion 4 | Co-existence of multiple barriers described above | Pan-RAS inhibitors | Pan-RAS inhibitors broadly target multiple KRAS mutations while exerting dual effects of direct antitumor activity and TME remodeling |
Activated KRAS signaling not only drives autonomous tumor cell proliferation but also actively reprograms the TME, ultimately establishing a prototypical “cold tumor” phenotype. This immunosuppressive milieu is characterized by profound T cell dysfunction and exhaustion, extensive infiltration of immunosuppressive cell populations such as MDSCs, and dense stromal fibrosis driven by the tumor stroma [4–6]. Collectively, these features create formidable barriers to effective antitumor immune responses. Immune evasion within the KRAS-mutant TME is mediated predominantly through the following mechanisms:
Suppression and exhaustion of immune cell function
Mutant KRAS signaling drives persistent activation of downstream pathways that stimulate tumor cells and stromal components to secrete a broad array of immunomodulatory cytokines, including granulocyte–macrophage colony-stimulating factor (GM-CSF), interleukin-6 (IL-6), IL-8, IL-10, and transforming growth factor-β (TGF-β). Together, these factors establish a profoundly immunosuppressive tumor microenvironment [4, 6, 34]. Among these mediators, GM-CSF plays a central role in promoting the accumulation and activation of MDSCs within the TME. Activated MDSCs suppress antitumor immunity by secreting arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS), leading to depletion of arginine and increased production of nitric oxide (NO). These metabolic alterations directly impair CD8⁺ T cell effector function and induce T cell apoptosis [4, 5, 35]. L-6, in cooperation with TGF-β, further drives the polarization of tumor-associated macrophages(TAMs)toward an immunosuppressive M2 phenotype and enhances the suppressive activity of Tregs [34, 36, 37]. IL-8 facilitates the recruitment of tumor-associated neutrophils (TANs) and, together with TGF-β, promotes their polarization toward the pro-tumorigenic N2 phenotype. Polarized TANs exacerbate CD8⁺ T cell dysfunction through MDSC-like metabolic mechanisms, including elevated Arg-1 expression, thereby accelerating T cell exhaustion [6, 35]. IL-10 contributes to immune evasion by inhibiting the maturation of dendritic cells (DCs) and downregulating major histocompatibility complex class II (MHC-II) expression on their surface, which compromises their capacity to prime naïve CD4⁺ T cells [36, 38]. In addition to cytokine-mediated effects, oncogenic KRAS signaling directly upregulates programmed death-ligand 1 (PD-L1) expression on tumor cells through pathways such as MAPK signaling. Engagement of PD-L1 with programmed death-1 (PD-1) on CD8⁺ T cells transmit potent inhibitory signals that culminate in T cell exhaustion [4, 5]. Concurrently, downstream KRAS signaling suppresses the expression of major histocompatibility complex class I (MHC-I) molecules on tumor cells, thereby impairing cytotoxic T lymphocyte recognition and facilitating immune escape [6, 39]. (Fig. 2)
Fig. 2.
Mechanisms of KRAS-driven immune suppression and T cell exhaustion in the tumor microenvironment. This schematic illustrates how oncogenic KRAS mutations establish an immunosuppressive tumor microenvironment (TME). (a) In cancer cells, mutant KRAS activates downstream signaling pathways including RAF-MEK-ERK (MAPK cascade) and PI3K-AKT-mTOR. These signals directly upregulate programmed death-ligand 1 (PD-L1) expression while suppressing major histocompatibility complex class I (MHC-I) expression, enabling CD8⁺ T cell evasion via PD-L1/PD-1 engagement and impaired antigen presentation. (b) Mutant KRAS signaling also stimulates tumor cells and stromal components to secrete immunomodulatory cytokines (GM-CSF, IL-6, IL-8, IL-10, TGF-β), which orchestrate broad immunosuppression. GM-CSF promotes myeloid-derived suppressor cell (MDSC) accumulation and activation; MDSCs suppress CD8⁺ T cells through arginase-1 (Arg-1)-mediated arginine depletion and inducible nitric oxide synthase (iNOS)-mediated nitric oxide (NO) production. IL-6 and TGF-β drive M2 polarization of tumor-associated macrophages (TAMs) and enhance regulatory T cell (Treg) suppressive activity. IL-8 together with TGF-β recruits tumor-associated neutrophils (TANs) and promotes their N2 polarization; N2 TANs further impair CD8⁺ T cells via Arg-1. IL-10 inhibits dendritic cell (DC) maturation and downregulates MHC-II expression, compromising CD4⁺ T cell priming. Collectively, these interconnected pathways establish a coordinated network that sustains tumor immune evasion and progression
Physical barriers
Sustained oncogenic KRAS signaling drives the activation of pancreatic stellate cells (PSCs), promoting their transdifferentiation into CAFs. Activated CAFs secrete excessive amounts of extracellular matrix (ECM) components, resulting in the formation of a dense desmoplastic stroma that constitutes a formidable physical barrier. This barrier severely restricts the infiltration of cytotoxic T lymphocytes into the tumor core and markedly impairs the intratumoral delivery of therapeutic agents [5, 6, 39]. In parallel, CAFs themselves secrete immunosuppressive cytokines such as IL-6 and TGF-β, further reinforcing the immunosuppressive state of the tumor microenvironment [6, 34].Beyond their structural role, specific CAF subpopulations actively modulate immune cell trafficking. These CAF subsets constitutively secrete the chemokine CXCL12, which engages the CXCL12–CXCR4 signaling axis to induce a phenomenon termed “chemokine-mediated immune exclusion.” Through this mechanism, T cells are actively recruited but sequestered within the stromal compartment, thereby preventing their direct contact with malignant epithelial cells [6, 37].To target this mechanism, several clinical trials are currently underway, including a Phase IIb study evaluating the CXCR4 antagonist BL-8040 in combination with pembrolizumab for the treatment of metastatic pancreatic cancer (NCT02907099). (Fig. 3)
Fig. 3.
Physical barriers and metabolic reprogramming within the tumor microenvironment. This schematic illustrates two core mechanisms by which oncogenic KRAS signaling establishes an immunosuppressive tumor microenvironment. (a) Stromal barriers. Sustained KRAS activation drives pancreatic stellate cell transdifferentiation into cancer-associated fibroblasts (CAFs), which deposit excessive extracellular matrix (ECM) to form a dense desmoplastic stroma that physically restricts T cell infiltration and impairs drug delivery. CAF subsets also secrete CXCL12, engaging the CXCL12-CXCR4 axis to actively sequester T cells within the stroma (chemokine-mediated immune exclusion). (b) Metabolic reprogramming. Through sustained MAPK signaling, mutant KRAS upregulates glycolytic rate-limiting enzymes (GLUT1, HK2, PKM2), enforcing the Warburg effect (aerobic glycolysis). This leads to avid glucose consumption and local glucose deprivation, which severely compromises CD8⁺ T cell effector function. Concurrently, KRAS upregulates glutaminase 1 (GLS1) to promote glutamine catabolism, sustaining anabolic growth and metabolic homeostasis. Hyperactive glycolysis also causes excessive lactate accumulation and microenvironmental acidification, which directly suppresses CD8⁺ T and NK cell cytotoxicity while promoting immunosuppressive populations (Tregs and M2-polarized TAMs). Metabolic competition and acidification synergistically exacerbate immune evasion
Metabolic reprogramming
Metabolic reprogramming driven by oncogenic KRAS represents a central mechanism in the establishment of an immunosuppressive tumor microenvironment. Through sustained activation of downstream pathways such as MAPK signaling, mutant KRAS upregulates the expression of key rate-limiting enzymes involved in glycolysis, including glucose transporter 1 (GLUT1), hexokinase 2 (HK2), and pyruvate kinase M2 (PKM2). This metabolic shift enforces a pronounced “Warburg effect,” whereby tumor cells preferentially rely on aerobic glycolysis even under normoxic conditions [7–9].As a consequence, cancer cells avidly consume glucose within the microenvironment, leading to local glucose deprivation that severely compromises the effector function of CD8⁺ T cells, which are highly dependent on glycolytic metabolism for activation and cytotoxicity. In addition to enhanced glycolysis, KRAS-mutant PDAC cells exhibit a strong dependence on glutamine metabolism. By upregulating glutaminase 1 (GLS1), oncogenic KRAS promotes glutamine catabolism to sustain anabolic growth and metabolic homeostasis [7, 8]. Concurrently, hyperactive glycolysis results in excessive lactate accumulation within the TME, generating an acidic microenvironment. Elevated lactate levels not only directly suppress the cytotoxic activity of CD8⁺ T cells and natural killer (NK) cells but also promote the differentiation and function of immunosuppressive populations, including Tregs and M2-polarized TAMs. Thus, metabolic competition and microenvironmental acidification synergistically exacerbate immune evasion in KRAS-mutant PDAC [6, 7, 40]. (Fig. 3)
Collectively, KRAS mutations orchestrate a profoundly immunosuppressive TME in PDAC through the coordinated suppression of immune cell function, the establishment of dense fibrotic barriers, and extensive metabolic reprogramming. This multilayered immune-evasive ecosystem underlies the repeated failure of ICI monotherapy in this disease. Consequently, future therapeutic strategies must move beyond single-axis interventions and instead focus on rational combination approaches that simultaneously target oncogenic KRAS signaling, remodel the stromal barrier, and reverse metabolic constraints. Such integrated strategies hold promise for systematically reprogramming the PDAC tumor ecosystem and unlocking durable antitumor immune responses.
Challenges of immunotherapy and the exploration of novel therapeutic paradigms (Table 2)
Table 2.
Trials of Immunotherapy in PDAC. Data acquired from ClinicalTrials.gov.Additional sources: *ASCO; #PubMed; ¥ESMO, &BMJ
| NCT | Phase | Intervention | Study Participant | Clinical Outcomes | Study Initiation |
|---|---|---|---|---|---|
| NCT01417000 | II |
Arm A: Clophosphamide +GVAX + CRS-207 Arm B: Cyclophosphamide +GVAX |
Metastatic Pancreatic Adenocarcinoma |
OS: 6.28 mo in Arm A(4.47–9.40) 4.07 mo in Arm B(3.32–5.42) |
2011- |
| NCT01896869 | II |
Arm A: Ipilimumab + GM-CSF Vaccine Arm B༚FOLFIRINOX |
Metastatic Pancreatic Adenocarcinoma |
OS: 9.38 mo in Arm A(5.0-12.2) 14.7 mo in Arm B(11.6–20.2) PFS: 2.40 mo in Arm A(1.87–2.53) 5.55 mo in Arm B(3.32–8.51) |
2013- |
| NCT02004262 | IIb |
Arm A: Cyclophosphamide +GVAX + CRS-207 Arm B: CRS-207 Arm C：Chemotherapy |
2nd-line, 3rd-line and Greater Metastatic Pancreatic Cancer |
OS: 4.2 mo in Arm A(3.0-5.4) 5.2 mo in Arm B(4.2–6.3) 4.7 mo in Arm C(3.8-6.0) |
2014- |
| NCT02045589# | I |
Single Arm: VCN-01 Oncolytic Adenovirus + Gemcitabine + Abraxane®;Dose Escalation, Combination |
Advanced Pancreatic Cancer | Treatment was generally well-tolerated and resulted in disease stabilization of injected lesions | 2014- |
| NCT02362048 | II |
Arm A: ACP-196 Arm B༚ACP-196 + pembrolizumab |
Advanced or Metastatic Pancreatic Cancer |
ORR: 0.0% in Arm A(0/29) 11.1% in Arm B(3/27) |
2015- |
| NCT02620423 * | Ib |
Single Arm: REOLYSIN® (Oncolytic Adenovirus)+Chemotherapy༈Gemcitabine, Irinotecan or Leucovorin/ 5-FU)+Pembrolizumab |
Advanced Pancreatic Adenocarcinoma |
The combination therapy showed manageable safety profiles and antitumor activity | 2015- |
| NCT02451982# | II |
Arm A: Cyclophosphamide + GVAX Pancreas Vaccine Arm B: Cyclophosphamide + GVAX Pancreas Vaccine + Nivolumab Arm C: Cyclophosphamide + GVAX Pancreas Vaccine + Nivolumab + Urelumab(CD137 Agonist) |
Surgically Resectable Adenocarcinoma of the Pancreas |
All treatments are well-tolerated. mDFS: 13.90 mo in Arm A; 14.98 mo in Arm B ; 33.51 mo in Arm C. mOS: 23.59 mo in Arm A; 27.01 mo in Arm B; 35.55 mo in Arm C. |
2016- |
| NCT02777710* | I | Single Arm: Durvalumab + Pexidartinib(CSF-1R Tyrosine Kinase Inhibitor) |
Advanced or Metastatic Pancreatic Cancer |
The combination therapy showed manageable safety profiles |
2016- |
| NCT02907099 | IIb |
Single Arm: BL-8040 (CXCR4 Antagonist)+Pembrolizumab |
Metastatic Pancreatic Cancer | ORR: 6.7%(1/15) | 2016- |
| NCT02705196# | I/IIa |
Arm A: LOAd703(oncolytic virus encoding TMZ-CD40L and 4-1BBL)+ Gemcitabine + Nab-paclitaxel Arm B: LOAd703(oncolytic virus encoding TMZ-CD40L and 4-1BBL)+ Gemcitabine + Nab-paclitaxel+ Atezolizumab |
Unresectable or metastatic Pancreatic Cancer |
Arm A: Manageable safety profile; ORR: 44%(95% CI 25%–66%); DCR;94%(95% CI 74%–99%). Arm B: Results have not yet been published. |
2016- |
| NCT03098550 | I/II | Single Arm: Nivolumab + Daratumumab |
Advanced or Metastatic Pancreatic Adenocarcinoma |
ORR: 0% mPFS: 1.22 mo(1.15–1.38) |
2017- |
| NCT03168139# | I/II |
Arm A: Olaptesed pegol(CXCL12 inhibitor); Monotherapy Arm B: Olaptesed pegol + Pembrolizumab༛Combination Therapy |
Metastatic Pancreatic Cancer |
The CXCL12 inhibitor olaptesed pegol demonstrated a manageable safety profile with no unexpected toxicities. Arm B: ORR༚0%; DCR: 22%(2/9) |
2017- |
| NCT03193190 | Ib/II |
Cohort 1: Arm A: Control (Gnp) Arm B: Atezolizumab (anti-PD-L1) + Selicrelumab (agonist CD40 Ab) + GnP Arm C: Atezolizumab + Bevacizumab (anti-VEGF-A) + GnP Arm D: Atezolizumab + AB928 (dual adenosine receptor antagonist) + GnP Arm E: Atezolizumab + Tiragolumabb(TIGIT inhibitor)+ GnP Arm F: Atezolizumab + Tocilizumab (IL-6R inhibitor )+Gnp Cohort 2: Arm G: Control (mFOLFOX6) Arm H: Control (Gnp) Arm I: Atezolizumab + BL-8040 (CXCR4 antagonist) Arm J: Atezolizumab + Cobimetinib(MEK inhibitor) Arm K: Atezolizumab + PEGPH20 Arm L: Atezolizumab + RO6874281 Q3W (immunocytokine-targeting FAP) Arm M: Atezolizumab + RO6874281 Q2W |
Metastatic PDAC (Morpheus-Pancreatic Cancer) |
ORR: 37.5%(21.10-56.31)in Arm A; 55.6%(21.20–86.30)in Arm B; 48.0.% (27.8-68.69)in Arm C; 26.7% (7.79–55.10)in Arm D; 31.7%(18.08–48.09)in Arm E; 30%(14.73–49.40)in Arm F 8.7%(1.07–28.04)in Arm G; 0% in Arm H; 0% in Arm I; 0% in Arm J; 6.1%(1.68–14.80)in Arm K; 0% in Arm L; 7.1% (0.18–33.87)in Arm M. |
2017- |
| NCT03190265 | II |
Arm A: Cyclophosphamide + Nivolumab + Ipilimumab + GVAX Pancreas Vaccine + CRS-207 Arm B: Nivolumab+Ipilimumab + CRS-207 |
Previously Treated Metastatic Pancreatic Adenocarcinoma |
ORR: 0% in Arm A(29) 7.4% in Arm B(2/27) |
2017- |
| NCT03250273 | II | Single Arm: Entinostat + Nivolumab |
Metastatic or Unresectable Pancreatic Cancer |
ORR: 11.1%(3/27) | 2017- |
| NCT03264404 | II |
Single Arm: Pembrolizumab + Azacitidine |
Advanced Pancreatic Cancer After Failure of First-Line Therapy |
mPFS: 1.49 mo (1.38–1.74) ORR: 9.7% DCR;35.5% |
2017- |
| NCT03252808* | I |
Arm A: TBI-1401( HSV-1 Oncolytic Virus)+Gemcitabine + Nab-paclitaxel Arm B: TBI-1401(HF10༉+ TS-1(primary) Arm C: TBI-1401 + TS-1 (primary and meta) |
Stage III or IV Unresectable Pancreatic Cancer. |
Recommended dose of TBI-1401 in combination with GnP: 1 × 10⁷ TCID₅₀/mL (intratumoral injection, every 2 weeks). The combination of TBI-1401 and standard chemotherapy demonstrated a favorable benefit/risk profile with no dose-limiting toxicities observed |
2017- |
| NCT03331562 | II |
Arm A: pembrolizumab + Paricalcitol(VitD Receptor Agonist) Arm B: Pembrolizumab + Placebo |
Stage IV Pancreatic Cancer Who Have Been Placed in Best Possible Response |
6-month PFS;0% in Arm A༛ 16.7% in Arm B |
2017- |
| NCT03006302 | II |
Arm A: Epacadostat(anti-IDO1)+ Pembrolizumab +Cyclophosphamide + GVAX followed by CRS-207+ Epacadostat + Pembrolizumab; Dose Escalation Arm B: Epacadostat+Pembrolizumab+ CRS-207;Dose Expansion |
Metastatic Pancreatic Adenocarcinoma and have progressed on prior chemotherapy. |
Maximum Tolerated Dose (MTD) of Epacadostat: 600 mg BID; 6 Months OS: 46.2%(12/26) |
2018- |
| NCT03767582* | I/II |
Arm A: SBRT+Nivolumab + BMS-813,160 Arm B：SBRT+GVAX+Nivolumab+ BMS-813,160(CCR2/CCR5 dual antagonist) |
Locally Advanced PDACs | The combination therapy demonstrated a manageable safety profile, and no dose-limiting toxicities were observe | 2019- |
| NCT04117087# | I |
Single Arm: KRAS Vaccine Peptide + Nivolumab + Ipilimumab |
Resected Mismatch Repair Protein (MMR-p) Pancreatic Cancer |
The combination regimen was safe and manageable, with no unexpected toxicity signals observed.; DFS: 6.35 mo; OS: 29.59 mo |
2020- |
| NCT04157127 | I | Single Arm: Th-1 DC immunotherapy vaccine | Potentially Resectable PDAC Following Completion of Standard Chemotherapy | Final data not yet published | 2020- |
| NCT04332653* | Ib/IIa | Single Arm: NT-I7 + Pembrolizumab | Naïve Relapsed or Refractory Pancreatic Cancer Pancreatic Cancer |
mOS: 11.1 mo in PDAC [95% CI 4.1–13.3 mo]; ORR: 4.2%(2/48) DCR: 25.0%(12/48) PFS: 1.4 mo |
2020- |
| NCT04404595* | I/II | Single Arm: anti-claudin18.2 CAR-T |
Advanced Pancreatic Adenocarcinoma |
ORR: 16.7%(2/12); mDOR: 3.4 mo; CBR: 33.3% |
2020- |
| NCT04581473* | Ib/II |
Arm A: anti-claudin18.2 CAR-T Arm B༚Best support care (Paclitaxel or Irinotecan or Apatinib or Anti-PD-1 antibody) |
Advanced Pancreatic Adenocarcinoma |
DCR: 70.8% mPFS: 3.3 mo (95% CI, 1.8 to 6.2) mOS: 10.0 mo (95% CI, 5.5 to 17.6) |
2020- |
| NCT04888312* | Ib/II |
Single Arm: Mitazalimab 900 µg/kg (CD40 agonist )+ mFOLFIRINOX |
Metastatic PDAC |
mOS: 14.9 mo; DCR: 78.9% mPFS: 77 mo; |
2021- |
| NCT05482451# | I | Single Arm: Nivolumab + ATRA | Refractory Pancreatic Cancer |
A higher dose of ATRA combined with nivolumab significantly prolonged mOS |
2021- |
| NCT05650918# | I |
Single Arm: MesoPher(DCs Loaded With Allogeneic Tumor Lysate )+ Mitazalimab(CD40 Agonist) |
Metastatic Pancreatic Cancer after SOC Treatment with mFOLFIRINOX. |
MesoPher/mitazalimab combination therapy demonstrates a favorable safety and tolerability profile. mPFS:1.9 mo; mOS:4.4 mo; 1-yeaar PFS:6.3%; DCR: 50%(8/16) (In non-PD at baseline patients, mPFS and mOS were 2.76 and 12.1 mo.) |
2021- |
| NCT05014776 | II |
Single Arm: Tadalafil+Pembrolizumab+ Ipilimumab + CRS-207 |
Previously Treated Metastatic Pancreatic Adenocarcinoma | Final data not yet published | 2022- |
| NCT05052723 | II |
Single Arm: Cabozantinib + Pembrolizumab |
Metastatic Pancreatic Cancer |
1-year PFS: 9.5%(2/21) ORR: 4.8%(1/21) 1-year OS: 9.5%(2/21) |
2022- |
| NCT05162118& | I/II | Single Arm: Recombinant Human IL12/15-PDL1B Oncolytic HSV-1 Injection + Nivolumab | Advanced Pancreatic Cancer |
ORR: 9.1%; DCR: 23.1% |
2022- |
| NCT05419479 | Ib/II |
Arm A: Zimberelimab(anti-PD-1)+ Domvanalimab(anti-TIGIT)+APX005M༈CD40 Agonist༉ Arm B: FOLFIRI |
Metastatic Pancreatic Cancer | Final data not yet published | 2022- |
| NCT06006390 | I/II |
Arm A: CEA-targeted CAR-T cells; intravenous infusion Arm B: CEA-targeted CAR-T cells; intraperitoneal injection |
Advanced Pancreatic Adenocarcinoma; Subjects will receive conditioning therapy by Fludarabine and Cyclophosphamide before cell infusion. |
Final data not yet published | 2023 |
| NCT05673811¥ | IIb |
Arm A: Nab-paclitaxel + Gemcitabine Arm B༚VCN-01 + Nab-paclitaxel + Gemcitabine |
Metastatic Pancreatic Cancer |
mOS: 8.6 mo in Arm A; 10.8 mo in Arm B; mPFS: 4.6 mo in Arm A; 7.0 mo in Arm B; ORR: 31.3% in Arm A; 39.6% in Arm B; |
2023- |
| NCT05916261 | I |
Arm A: Personalized neoantigen tumor vaccine(mRNA-0217/S001 vaccine ); Dose Escalation Arm B: Personalized neoantigen tumor vaccine+ Pembrolizumab; Dose Expansion |
Advanced Pancreatic Cancer | Final data not yet published | 2023- |
| NCT05964361 | I/II |
Single Arm: IL15/IL15Ra/WT1 DC vaccine |
Refractory or Advanced Pancreas Cancer |
Final data not yet published | 2023- |
| NCT05927142 | Ib/II | Single Arm: Durvalumab + Rintatolimod(TLR-3 Agonist) | Metastatic Pancreatic Cancer | Final data not yet published | 2024- |
| NCT06015724 | II |
Single Arm: Daratumumab( anti-CD38 mAb)+KRAS vaccine+ Nivolumab |
Pancreatic Cancer | Final data not yet published | 2024- |
| NCT06326736 | I | Single Arm : Surgery+Camrelizumab + SJ-Neo006(Neoantigen mRNA Vaccines)+Emcitabine + Abraxane | Resectable Pancreatic Cancer | Final data not yet published | 2024- |
| NCT06496373 | I | Single Arm: XP-004 Personlaized mRNA Vaccine + Toripalimab(anti-PD-1) | Chemotherapy-intolerant and Resectable Pancreatic Cancer | Final data not yet published | 2024- |
| NCT06577532 | I |
Arm A: ABO2102(KRAS neoantigen mRNA vaccine );Monotherapy Arm B༚ABO2102 + Toripalimab༈ anti-PD-1);Combination |
KRAS-mutated Advanced Pancreatic Cancer | Final data not yet published | 2024- |
| NCT06758544 | I/II |
Single Arm: Oncolytic virus VRT106+ Chemotherapy |
Resectable Pancreatic Cancer | Final data not yet published | 2025- |
| NCT07006077 | II |
Single Arm: Recombinant human IL-21-expressing oncolytic vaccinia virus injection |
Advanced Pancreatic Tumors | Final data not yet published | 2025- |
| NCT06782932 | I/II |
Arm A: AGEN2373(CD137 Agonist)+ Balstilimab༈anti-PD-1༉+ Cyclophosphamide + GVAX Arm B: AGEN2373 + Balstilimab+ mKRASvax |
Surgically Resectable Pancreatic Adenocarcinoma |
Final data not yet published | 2025- |
| NCT07066995 | I/II |
Single Arm: Dual-Target CAR-T (Mesothelin and Claudin 18.2 + Cyclophosphamide + Fludarabine Phosphate |
Advanced or Metastatic Pancreatic Cancer |
Final data not yet published | 2025- |
ICIs have achieved transformative clinical success in multiple solid tumors, including non-small cell lung cancer and melanoma. However, their efficacy in PDAC—particularly in the predominant KRAS-mutant subtype—remains extremely limited [10]. This striking disparity is largely attributable to the distinctive TME of PDAC, which is characterized by profoundly insufficient infiltration of effector T cells and extensive accumulation of immunosuppressive populations, such as Tregs, M2-polarized macrophages, and MDSCs. In addition, the dense desmoplastic stroma that typifies PDAC forms a formidable physical barrier, severely impeding both drug delivery and immune cell trafficking into the tumor bed [11, 41, 42].
To date, clinical investigations of ICIs in PDAC have primarily focused on targeting the CTLA-4 and PD-1/PD-L1 pathways. Anti–CTLA-4 antibodies act at the early phase of T cell activation by blocking the interaction between CTLA-4 and B7 molecules on antigen-presenting cells, thereby restoring CD28-mediated costimulatory signaling. Moreover, anti–CTLA-4 therapy may alleviate immunosuppression by depleting intratumoral Tregs through antibody-dependent cellular cytotoxicity (ADCC) [43].In contrast, antibodies targeting PD-1 or PD-L1 exert their effects predominantly during the effector phase of T cell responses, reversing T cell exhaustion by disrupting PD-1 engagement with its ligands PD-L1 or PD-L2 and thereby restoring antitumor activity and cytotoxic function.
Despite these mechanistic rationales, clinical studies have consistently highlighted the limitations of ICI monotherapy in PDAC. In a phase II trial conducted by Royal et al., ipilimumab monotherapy in patients with advanced pancreatic cancer yielded an objective response rate (ORR) of 0%, with a median overall survival (OS) of only 4.3 months [10] .Similarly, a study led by Callahan et al. evaluated nivolumab alone or in combination with ipilimumab, with exploratory cohorts incorporating the MEK inhibitor cobimetinib, and likewise failed to demonstrate objective responses in previously treated patients with advanced PDAC [44]. Collectively, these findings underscore that, in KRAS-mutant pancreatic cancer, immune checkpoint blockade alone is insufficient to overcome the deeply entrenched immunosuppressive tumor microenvironment. Consequently, there is an urgent need to develop and implement novel immunotherapeutic paradigms capable of reshaping this hostile ecosystem and unlocking effective antitumor immunity.
CAR-T cell therapy
CAR-T cell therapy employs genetic engineering to endow T cells with synthetic antigen receptors that specifically recognize tumor-associated antigens, thereby enabling targeted and potent cytotoxicity against malignant cells [13]. However, the clinical application of CAR-T therapy in solid tumors (including neuroendocrine tumors and pancreatic cancer) continues to face multiple challenges. The immunosuppressive tumor microenvironment and its physical barriers (such as the dense stroma) severely restrict CAR-T cell infiltration and durable functionality, while heterogeneous target antigen expression and the potential risk of “on-target, off-tumor” toxicity further compromise its efficacy and safety. Additionally, exorbitant treatment costs preclude its widespread adoption as a routine therapeutic modality. Consequently, this therapy is currently more suitable as an individualized experimental approach for patients with highly aggressive disease who lack other effective treatment options [45].To overcome these obstacles, recent explorations of CAR-T targets in pancreatic cancer have yielded positive progress. Current investigations into CAR-T therapy for PDAC have primarily focused on tumor-associated antigens such as GAS6, Claudin 18.2 (CLDN18.2), and mesothelin [46].Preclinical studies have demonstrated that GAS6-targeted CAR-T cells effectively eradicate pancreatic cancer cells, including therapy-resistant populations and cancer stem-like cells, while exhibiting a favorable safety profile [47]. Early clinical evidence further supports the feasibility of this approach. In a preliminary clinical study, three patients with advanced pancreatic cancer received CLDN18.2-directed CAR-T cell therapy, resulting in one complete response (CR) and two partial responses (PR), indicating notable initial antitumor activity. However, this study also reported gastric mucosal injury attributable to antigen expression overlap between tumor and normal tissues. Although the associated toxicity was successfully managed with cyclophosphamide in combination with cetuximab, these findings underscore the persistent risk of “on-target, off-tumor” toxicity that remains a major challenge for CAR-T therapy in solid tumors [48]. Moreover, the profoundly immunosuppressive tumor microenvironment, dense stromal barriers, and pronounced antigen heterogeneity characteristic of pancreatic cancer severely limit CAR-T cell infiltration, persistence, and sustained antitumor efficacy [13, 46].
Consequently, despite its promising potential, the application of CAR-T cell therapy in KRAS-mutant PDAC remains at an early exploratory stage. Future progress will depend on the identification of more tumor-specific antigens and the development of rational combination strategies designed to overcome the immunosuppressive microenvironment and physical barriers inherent to this disease.
Oncolytic virus (OV) therapy
OVs selectively replicate within tumor cells and induce tumor cell lysis, leading to the release of tumor antigens and the initiation of in situ antitumor immune responses. This mechanism offers a unique strategy to convert the immunologically “cold” TME characteristic of KRAS-mutant PDAC into an immune-active state [14]. A genetically engineered oncolytic vaccinia virus lacking the TK, N1L, and A41L genes and expressing interleukin-27 (IL-27) has been shown to promote robust CD8⁺ T cell infiltration, induce M1 macrophage polarization, reduce Treg abundance, and inhibit tumor angiogenesis, ultimately achieving complete tumor regression in murine models [49]. In another study, the p53-armed oncolytic adenovirus OBP-702, when combined with the AG chemotherapy regimen, not only suppressed primary tumor growth but also elicited systemic antitumor effects. This combination activated long-lived memory CD8⁺ T cells, established durable immune surveillance, and significantly reduced the risk of tumor recurrence [50].In addition to immune suppression, the PDAC stroma is enriched in hyaluronic acid, which elevates interstitial fluid pressure and compresses tumor vasculature, thereby severely limiting the penetration of chemotherapeutic agents and immune cells. Although preclinical studies demonstrated that the hyaluronidase PEGPH20 effectively alleviates this physical barrier, the phase III HALO 109–301 clinical trial revealed that PEGPH20 in combination with AG chemotherapy failed to improve OS in patients with PDAC. These findings suggest that stromal-targeting strategies may require integration with additional immunomodulatory approaches to achieve meaningful clinical benefit [51].Against this backdrop, the oncolytic adenovirus VCN-01 has been developed to simultaneously degrade the dense ECM of KRAS-mutant PDAC through the expression of hyaluronidase and exert potent oncolytic and immune-stimulatory effects [52]. A phase I clinical trial demonstrated the feasibility of this approach, with most patients exhibiting acceptable tolerability. However, one patient receiving a high-dose treatment experienced fatal hemorrhage associated with rapid tumor necrosis, highlighting the potential safety risks accompanying strong oncolytic activity and underscoring the importance of careful dose optimization and risk management in future clinical development [52].
Despite their considerable promise, the clinical translation of oncolytic virus therapies faces multiple challenges, including efficient viral delivery, host antiviral immune responses, and achieving sufficient tumor specificity. Future research should focus on optimizing viral vector design, exploring rational combinations with chemotherapy, radiotherapy, and immunotherapeutic agents, and implementing rigorous monitoring and management of OV-associated toxicities.
Targeting costimulatory signals to activate T cells
Targeting T cell costimulatory signaling pathways represents a promising strategy to alleviate the immunosuppressive tumor microenvironment in PDAC. Among these pathways, agonists of CD40, CD137 (4-1BB), and CD134 (OX40) have emerged as major areas of therapeutic interest.
CD40 agonists activate DCs, thereby enhancing T cell priming, activation, and expansion. In addition, CD40 signaling can reprogram TAMs from an immunosuppressive M2 phenotype toward a tumoricidal M1 state and may even promote stromal degradation [15, 53]. In an early neoadjuvant study involving patients with resectable pancreatic cancer, including individuals harboring KRAS mutations, treatment with the CD40 agonist selicrelumab in combination with the AG regimen (gemcitabine plus nab-paclitaxel) significantly improved median OS and progression-free survival (PFS) compared with CD40 monotherapy. Notably, this combination converted 82% of tumors into a T cell–enriched phenotype, highlighting its capacity to remodel the tumor immune microenvironment [54]. Consistently, the phase II PRINCE trial demonstrated that although the clinical benefit of sotigalimab combined with chemotherapy was modest, this regimen markedly enhanced CD4⁺ T cell infiltration and antigen-presenting cell activation, indicating robust immunomodulatory activity [16].
Compared with CD40 agonists, clinical data on CD137 and CD134 agonists in PDAC remain limited, with most studies focusing on combination strategies. In preclinical PDAC models harboring KRAS mutations, a therapeutic regimen combining the GVAX cancer vaccine with pembrolizumab (a PD-1 inhibitor) and the CD137 agonist urelumab synergistically enhanced T cell activation, promoted the generation of effector memory T cells, and reversed T cell exhaustion, leading to significantly prolonged survival in treated animals [55]. In another study, a bispecific antibody simultaneously targeting PD-L1 and CD134 (EMB-09) demonstrated promising activity in both KRAS-mutant preclinical models and early clinical evaluation. In preclinical settings, EMB-09 exhibited superior antitumor efficacy and a favorable safety profile compared with PD-L1 monotherapy. Subsequently, in a phase I clinical trial, one patient with KRAS G12D –mutant PDAC achieved a durable clinical response [56].
Collectively, these studies suggest that T cell–activating agents, when combined with chemotherapy, ICIs, or cancer vaccines, hold significant potential to overcome the immunosuppressive microenvironment of KRAS-mutant PDAC and to confer meaningful clinical benefit. Such combination strategies represent a compelling direction for future translational and clinical investigation.
Tumor vaccines
Tumor vaccines aim to activate tumor antigen–specific T cell responses by presenting tumor-derived antigens, thereby counteracting the immunosuppressive TME shaped by oncogenic KRAS signaling. Multiple vaccine platforms, including mRNA vaccines, DC vaccines, and whole-cell vaccines, have demonstrated encouraging clinical potential in PDAC.
mRNA vaccines stimulate antitumor immunity by encoding tumor-specific antigens (TSAs) and immunostimulatory molecules that direct immune responses against malignant cells [57]. Clinical follow-up data further demonstrated the efficacy of personalized mRNA vaccines administered in combination with standard-of-care therapy in patients with resectable PDAC.In this setting, 75% (6/8) of immune responders remained recurrence-free during the follow-up period, with durable immune protection and sustained antitumor surveillance. These findings provide compelling proof of principle supporting the development of vaccines targeting shared neoantigens, including mutant KRAS epitopes [58].
DC vaccines have also achieved notable progress in the treatment of PDAC.Engineered DC1 vaccines enhance intratumoral DC infiltration, promote effective T cell priming, and increase T cell receptor (TCR) repertoire diversity [59]. Clinical studies have shown that DC vaccines used as adjuvant therapy following surgical resection significantly improve patient outcomes, with 2-year recurrence-free survival (RFS) and OS rates of 64% and 83%, respectively. All treated patients developed vaccine-specific delayed-type hypersensitivity responses, underscoring the potent immune activation induced by this approach. Notably, molecular analysis of a long-term survivor revealed that both the primary tumor and metastatic lesions harbored the same KRAS G12D mutation, and vaccine-induced T cell infiltration was detected in metastatic sites. These observations suggest that DC vaccine–elicited immune responses can track and surveil KRAS-mutant tumor clones, providing a potential mechanism for delaying disease recurrence [60].
GVAX, a GM-CSF–secreting whole-cell vaccine, exerts its antitumor effects by stimulating T cell responses against tumor-associated antigens [61]. In patients with resectable pancreatic cancer, GVAX monotherapy demonstrated promising clinical activity, achieving a median OS of 35.0 months and a median disease-free survival (mDFS) of 18.4 months. Notably, GVAX treatment induced the formation of tertiary lymphoid aggregates (TLAs), and TLA density was strongly correlated with overall survival, suggesting that TLAs may serve as predictive biomarkers of vaccine efficacy [62].
These findings suggest that vaccine and ICI combination strategies possess synergistic potential, a conclusion that is well-supported in pancreatic cancer models. Specifically, the delivery of mMLKL mRNA via a POctS polymer-based carrier induces immunogenic cell death and upregulates PD-L1 expression, thereby sensitizing tumors to PD-L1 blockade; this combinatorial strategy significantly suppresses tumor growth and prolongs survival [63].Building on these preclinical foundations, a Phase I trial further validated the efficacy of a personalized mRNA neoantigen vaccine in combination with atezolizumab and an mFOLFIRINOX regimen in patients with surgically resected pancreatic cancer. In this cohort, 50% of patients developed robust and durable CD8⁺ T cell responses, which correlated with a significantly prolonged recurrence-free survival (RFS) [64]. Furthermore, this synergistic paradigm is similarly supported across other tumor types. For instance, combining a hollow mesoporous silica (HMS)–based cancer vaccine with one-eighth the standard dose of an anti-PD-L1 antibody achieved tumor growth inhibition comparable to full-dose monotherapy in a murine lymphoma model, while significantly reducing the incidence of immune-related adverse events (irAEs) [65].Similarly, in a murine melanoma model, the PeptiENV cancer vaccine combined with ICI therapy effectively controlled tumor growth and substantially improved the response rate to immune checkpoint blockade [66].
In summary, although the clinical efficacy of tumor vaccines in KRAS-mutant PDAC requires validation in larger, randomized trials, accumulating evidence highlights their therapeutic promise. Future efforts should focus on biomarker-driven patient selection and the rational integration of vaccines with chemotherapy, radiotherapy, ICIs, and targeted therapies, with the ultimate goal of delivering transformative immunotherapeutic strategies for patients with PDAC.
Exploration of combination therapeutic strategies
Radiotherapy combined with immunotherapy (Table 3)
Table 3.
Trials of Radiotherapy Combined with Immunotherapy in PDAC. All data acquired from ClinicalTrials.gov
| NCT | Phase | Intervention | Study Participant | Study Initiation |
|---|---|---|---|---|
| NCT01595321 | II |
Arm A: SBRT + FOLFIRINOX Arm B༚SBRT + mFOLFIRINOX Arm C༚Cyclophosphamide + GVAX +SBRT+ mFOLFIRINOX |
Resected Adenocarcinoma of the Pancreas | 2012- |
| NCT02648282 | II | Single Arm: Cyclophosphamide + GVAX Pancreas Vaccine +Pembrolizumab + SBRT | Locally Advanced Adenocarcinoma of the Pancreas | 2016- |
| NCT02866383 | II |
Arm A: Nivolumab + Radiotherapy Arm B༚Nivolumab + Ipilimumab + Radiotherapy |
Pretreated Patients with Metastatic Pancreatic Cancer |
2016 |
| NCT03104439 | II | Single Arm: Nivolumab + Ipilimumab + Radiation Therapy | Microsatellite Stable (MSS) and Microsatellite Instability (MSI) High Pancreatic Cancer | 2017- |
| NCT03161379 | II | Single Arm: Cyclophosphamide + GVAX Pancreas Vaccine+ Nivolumab + SBRT | Borderline Resectable Pancreatic Adenocarcinoma | 2018- |
| NCT04050085 | I | Single Arm: Nivolumab + Radiation Therapy+TLR9 Agonist SD-101 | Chemotherapy-Refractory Metastatic Pancreatic Adenocarcinoma | 2019- |
| NCT04098432 | I/II | Single Arm: Stereotactic radiotherapy + Nivolumab | Locally Advanced Unresectable Pancreatic Adenocarcinoma | 2018- |
| NCT04247165 | I/II | Single Arm: Nivolumab + Ipilimumab + Nab-paclitaxel + Gemcitabine + SBRT | Borderline Resectable, Locally Advanced or Metastatic Pancreatic Cancer | 2020- |
| NCT04361162 | II | Single Arm: Nivolumab + Ipilimumab + Radiation | Metastatic, Microsatellite Stable Pancreatic Cancer | 2020- |
| NCT05721846 | I | Single Arm: SBRT+ Nivolumab + Ipilimumab +GFβ-15 Peptide Vaccine | Refractory Pancreatic Cancer | 2023- |
| NCT06384560 | I/II | Single Arm: FOLFIRINOX + Pembrolizumab +SABR | Borderline Resectable Pancreatic Cancer | 2024- |
| NCT06843551 | II | Single Arm: SBRT+ Botensilimab + Balstilimab | Metastatic Pancreatic Cancer | 2025- |
Radiotherapy can induce immunogenic cell death, leading to the release of tumor antigens and damage-associated molecular patterns (DAMPs), thereby generating an “in situ vaccine” effect that activates systemic antitumor immune responses [67].In KRAS-mutant pancreatic cancer, the combination of radiotherapy and immunotherapy has the potential to reverse the immunosuppressive TME maintained by oncogenic KRAS signaling, enhance T cell infiltration, and convert localized tumor control into durable systemic antitumor immunity [68].The CheckPAC trial demonstrated that stereotactic body radiotherapy (SBRT) combined with nivolumab (anti–PD-1), with or without ipilimumab (anti–CTLA-4), achieved a clinical benefit rate of 37.2% and an ORR of 14.0% in patients with chemotherapy-refractory metastatic PDAC. These outcomes were markedly superior to those observed with ICI monotherapy, indicating that radiotherapy combined with sufficiently potent immunotherapy can partially overcome immune resistance in pancreatic cancer [17]. To further enhance therapeutic efficacy, Wang et al. evaluated hypofractionated radiotherapy in combination with a PD-1 antibody and SOX chemotherapy (S-1 plus oxaliplatin) as a second-line treatment. This regimen achieved a median PFS of 5.48 months, with an ORR of 30.4% and a median OS of 6.57 months, outperforming conventional chemotherapy [69].Given that oncogenic KRAS signaling sustains immune suppression through downstream MEK/ERK pathways, the incorporation of MEK inhibitors represents another important combinatorial strategy. In a phase II study, Zhu et al. reported that SBRT combined with pembrolizumab and the MEK inhibitor trametinib significantly prolonged both median PFS (8.2 months) and OS (14.9 months) in patients with advanced PDAC [70].
Collectively, these findings highlight the considerable promise of radiotherapy–immunotherapy combinations in KRAS-mutant PDAC. Future efforts should focus on optimizing combination regimens, leveraging predictive biomarkers to identify patients most likely to benefit, and advancing personalized radiotherapy planning—including target volume and dose optimization—to maximize therapeutic efficacy while minimizing treatment-related toxicity [71].
Chemotherapy combined with immunotherapy (Table 4)
Table 4.
Trials of Chemotherapy-Immunotherapy Combinations in PDAC. All data acquired from ClinicalTrials.gov
| NCT | Phase | Intervention | Study Participant | Study Initiation |
|---|---|---|---|---|
| NCT02309177 | I |
Arm A: Nab-paclitaxel + nivolumab Arm B: Nab-paclitaxel + Gemcitabine + Nivolumab |
Arm A: Adenocarcinoma of the pancreas with 1 prior systemic chemotherapy Arm A/B༚Adenocarcinoma of the pancreas with 1 prior systemic chemotherapyand subsequently no prior chemotherapy, surgery or radiation therapy for locally advanced or metastatic disease |
2015- |
| NCT02826486 | II |
Arm A: BL-8040 + pembrolizumab Arm B༚BL-8040 + pembrolizumab+Onivyde/5-FU/LV |
Arm A: Metastatic Pancreatic Cancer Arm B༚Metastatic pancreatic adenocarcinoma that have progressed following first-line treatment with gemcitabine-based chemotherapy |
2016- |
| NCT03563248 | II |
Arm A: FOLFIRINOX+SBRT+ Surgery Arm B༚FOLFIRINOX + Losartan + SBRT + Surgery Arm C༚FOLFIRINOX + Losartan+ SBRT+ Nivolumab + Surgery Arm D༚FOLFIRINOX + SBRT + Nivolumab +Surgery |
Localized Pancreatic Cancer | 2018- |
| NCT03970252 | I | Single Arm: Nivolumab + FOLFIRINOX +Therapeutic Conventional Surgery | Borderline Resectable Pancreatic Adenocarcinoma | 2019- |
| NCT03816358 | I |
Arm A: Anetumab ravtansine + Nivolumab Arm B༚Anetumab ravtansine + Nivolumab + Ipilimumab Arm C༚Anetumab ravtansine + Nivolumab + Gemcitabine |
Mesothelin positive pancreatic cancer | 2019- |
| NCT03697564 | II | Single Arm: Nivolumab + Cabiralizumab + Gemcitabine | Pancreatic Cancer Stage IV | 2019- |
| NCT04543071 | II | Single Arm: Motixafortide (CXCR4 inhibitor) + Cemiplimab + Gemcitabine + Nab-Paclitaxel | Treatment-naïve Metastatic Pancreas adenocarcinoma | 2020- |
| NCT04447092 | II |
Arm A: Gemcitabine + Nab-paclitaxel + Pembrolizumab Arm B༚FOLFIRINOX + Pembrolizumab |
Chemotherapy-naïve Advanced Pancreatic Cancer | 2020- |
| NCT04953962 | II |
Arm A: CBP501(25 mg/m2 )+ Cisplatin +Nivolumab Arm B: CBP501(16 mg/m2 )+ Cisplatin+ Nivolumab Arm C: CBP501(25 mg/m2)+cisplatin Arm D: Cisplatin + Nivolumab |
Exocrine Pancreatic Cancer and WBC < 10,000/mm3 at Screening | 2021- |
| NCT04731467 | I/II |
Arm A: CM24 + Nivolumab + Nab-paclitaxel+Gemcitabine; Expansion Arm B༚CM24 + nivolumab + Nal-IRI/5-FU/LV༛Expansion Arm C༚Nivolumab + Nab-paclitaxel + Gemcitabine༛Expansion Arm D༚Nivolumab + Nal-IRI/5-FU/LV; Expansion |
Advanced metastatic pancreatic cancer | 2021- |
| NCT06538207 | I |
Arm A: ONO-4578 + Nivolumab+mFOLFIRINOX Arm B༚ ONO-4578 + Nivolumab + Nab-paclitaxel+Gemcitabine |
Metastatic Pancreatic Cancer | 2021- |
| NCT06532344 | I |
Single Arm: ONO-7913 + Nivolumab+ mFOLFIRINOX |
Metastatic Pancreatic Cancer | 2021- |
| NCT04753879 | II | Single Arm: Nab-paclitaxel+Gemcitabine+Cisplatin+Irinotecan+Capecitabine+Pembrolizumab+Olaparib | Untreated Metastatic PDAC | 2021- |
| NCT05132504 | II | Single Arm: FOLFIRINOX + Pembrolizumab + Surgery | Localized, Resectable PDAC | 2022- |
| NCT06532331 | I |
Arm A: ONO-7475 + Nab-paclitaxel+Gemcitabine Arm B༚ONO-7475 + Nivolumab + Nab-paclitaxel+Gemcitabine |
Metastatic Pancreatic Cancer | 2023- |
| NCT05462496 | II | Single Arm: FOLFIRINOX +Ciprofloxacin +Metronidazole + Pembrolizumab + Surgical Resection | Resectable Pancreatic Cancer | 2023- |
| NCT05945823 | II | Single Arm: Futibatinib + Pembrolizumab + mFOLFIRINOX | Locally Advanced, Unresectable or Metastatic Pancreatic Cancer | 2023- |
| NCT06381154 | II | Single Arm: Photodynamic Therapy+ Verteporfin + Pembrolizumab + mFOLFIRINOX | Unresectable, Locally Advanced or Metastatic Pancreatic Cancer | 2024- |
| NCT06821503 | Ib/II |
Arm A: LM-108 + Penpulimab + Albumin paclitaxel+ Gemcitabine Arm B༚LM-108 + Albumin paclitaxel+ Gemcitabine |
Advanced Pancreatic Cancer | 2025- |
| NCT06941857 | II |
Arm A: FOLFIRINOX+NC410 + Nivolumab Arm B༚FOLFIRINOX+NC410 + Nivolumab+Ipilimumab |
Treatment-naïve, Metastatic Pancreatic Cancer | 2025- |
Beyond their direct cytotoxic effects on tumor cells, chemotherapeutic agents can actively modulate the TME and thereby enhance antitumor immunity. The FOLFIRINOX regimen has been shown to promote the activation of effector immune populations, including CD8⁺ T cells and T helper 1 (Th1) cells, while reducing the abundance of Tregs. In parallel, the AG regimen (gemcitabine plus nab-paclitaxel) can suppress tumor metabolism through activation of AMP-activated protein kinase (AMPK) signaling, collectively creating a more permissive environment for immunotherapy [72–74].Clinical evidence supporting chemotherapy–immunotherapy combinations has begun to emerge. In the phase II PRINCE trial reported by Padrón et al., first-line treatment with the AG regimen combined with nivolumab in patients with metastatic PDAC achieved a median PFS of 6.4 months and a median OS of 16.7 months, with an ORR of 50%. Notably, the 1-year OS rate was significantly higher than that of historical controls (57.7% versus 35%) [16].Similarly, a phase Ib/II study demonstrated that the combination of AG chemotherapy with pembrolizumab in chemotherapy-naïve patients with metastatic PDAC resulted in a median PFS of 9.1 months and a median OS of 15.0 months, indicating meaningful survival benefit [18].However, not all combination strategies have yielded positive results. In the phase II CCTG PA.7 trial, the addition of durvalumab (anti–PD-L1) and tremelimumab (anti–CTLA-4) to the AG regimen failed to produce a significant improvement in clinical outcomes. These findings suggest that intensifying immunotherapy in an unselected PDAC population does not necessarily translate into additional therapeutic benefit [75].
Collectively, these divergent clinical outcomes underscore the pronounced immunological heterogeneity of KRAS-mutant pancreatic cancer. Future combination strategies will need to incorporate refined patient stratification based on tumor microenvironmental features and predictive biomarkers to enable truly personalized therapeutic approaches.
Targeted Therapy Combined with Immunotherapy (Table 5 and Table 6)
Table 5.
Clinical Trials of Targeted Drugs in PDAC. All data acquired from ClinicalTrials.gov
| NCT | Phase | Intervention | Study Participant | Study Initiation |
|---|---|---|---|---|
| NCT02546531 | I |
Arm A: Defactinib + Pembrolizumab + Gemictabine; Dose escalation Arm B༚Defactinib + Pembrolizumab + Gemictabine ༛Dose expansion |
Advanced Pancreatic Cancer | 2016- |
| NCT02704156 | II |
Arm A: SBRT + Pembrolizumab + Trametinib Arm B༚SBRT + Gemcitabine |
Locally Recurrent Pancreatic Cancer After Surgical Resection | 2016- |
| NCT03404960 | Ib/II |
Arm A: Niraparib + Nivolumab Arm B༚Niraparib + Ipilimumab |
Advanced Pancreatic Cancer Whose Disease Has Not Progressed on Platinum-based Therapy | 2018- |
| NCT03600883 | I/II |
Arm A: Sotorasib(KRAS G12C inhibitor); Dose Exploration Arm B༚Sotorasib༛Dose Expansion Arm C༚Sotorasib + anti PD-1/L1;Combination |
KRAS p. G12C Mutated Advanced Pancreatic Cancer | 2018- |
| NCT03727880 | II |
Arm A: Pembrolizumab + Defactinib(FAK inhibitor) Arm B༚Pembrolizumab |
Resectable PDAC | 2019- |
| NCT03785249 | I/II | Single Arm: Adagrasib(KRAS G12C inhibitor)+ Cetuximab | Advanced Pancreatic Adenocarcinoma with KRAS G12C Mutation | 2019 |
| NCT03608631 | I/II | Single Arm: Mesenchymal Stromal Cells-derived Exosomes with KRAS G12D siRNA | Metastatic Pancreas Cancer Patients Harboring KRASG12D Mutation | 2021- |
| NCT04548752 | II |
Arm A: Olaparib(PARP Inhibitor )+ Pembrolizumab Arm B༚Olaparib |
Metastatic Pancreatic Cancer Patients with Germline BRCA1 or BRCA2 Mutations | 2021- |
| NCT05585320 | I/II |
Arm A: IMM-1( MEK1/2 Inhibitor)-104 + mGnP Arm B༚IMM-1-104 + mFOLFIRINOX |
Advanced or Metastatic pancreatic adenocarcinoma | 2022- |
| NCT06130254 | I | Single Arm: Adagrasib + Olaparib(PARP inhibitor) | KRAS p. G12C Mutated Advanced Pancreatic Cancer | 2024- |
| NCT06326736 | I | Single Arm: Surgery + Camrelizumab + SJ-Neo006(Neoantigen mRNA Vaccines)+ Gemcitabine + Nab-paclitaxel | Resectable Pancreatic Cancer | 2024- |
| NCT06599502 | I/IIa |
Arm A: AZD0022(KRAS G12D inhibitor); Dose Optimisation Arm B: AZD0022 + Cetuximab༚Dose Optimisation |
Advanced or metastatic PDAC with a KRAS p.G12D mutation | 2024- |
| NCT06747845 | II |
Arm A: Niraparib (PARP inhibitor)+ Ipilimumab Arm B༚FOLFIRI |
Metastatic Pancreatic Cancer Whose Disease Has Not Progressed on Platinum-Based Therapy | 2025- |
| NCT05093231 | II | Single Arm: Olaparib + Pembrolizumab | Metastatic Pancreatic Adenocarcinoma Patients with Mismatch Repair Deficiency or Tumour Mutation Burden > 4 Mutations/Mb | 2025- |
| NCT07020221 | I/II |
Arm A: VS-7375(KRAS G12D inhibitor.);Dose Expansion Arm B༚VS-7375 + Gemcitabine + Nab-Paclitaxel Dose༛Dose Escalation Arm C༚VS-7375 + Gemcitabine༛Dose Expansion |
Advanced KRAS G12D -Mutated PDAC | 2025- |
| NCT06818812 | I |
Arm A: INCB186748 Arm B༚INCB186748 + Cetuximab Arm C༚INCB186748 + GEMNabP Arm D༚INCB186748 + mFOLFIRINOX |
Advanced or metastatic PDAC with a KRAS p.G12D mutation | 2025- |
Table 6.
KRAS Mutation Subtypes in Pancreatic Cancer: Biology, Drug Sensitivity, and Immunotherapy Potential
| KRAS Subtype | Key Biological & Immune Features | Sensitivity to Targeted Therapies | Potential for Combination with Immunotherapy |
|---|---|---|---|
| G12D 1 |
Most prevalent subtype; drives early tumorigenesis. Promotes secretion of TGF-β and IL-10, suppressing CD8⁺ T cell function and establishing a “cold” tumor microenvironment. Induces epithelial-mesenchymal transition (EMT), facilitating cancer cell migration and invasion. |
G12D inhibitors (e.g., GFH375, MRTX1133): effective as monotherapy but ultimately leads to disease progression. Pan-RAS inhibitors: potential future direction |
Well-supported potential. Preclinical studies demonstrate that G12D inhibitors combined with multi-agent immunotherapy (e.g., CXCR2 inhibitor + LAG-3 antagonist + 4-1BB agonist) can induce durable complete responses |
| G12V 2 |
More aggressive signaling profile. Exhibits a “partially inflammatory” microenvironment: reduced secretion of immunosuppressive factors and higher T cell infiltration compared to G12D. |
MEK inhibitors: a potential target due to hyperactivation of the downstream MEK/ERK pathway. Pan-RAS inhibitors: potential future direction. |
Moderate potential. The relatively “warmer” microenvironment suggests possibly better response to immunotherapy following reversal of T cell dysfunction |
| G12R 3 | Exhibits a distinct signaling pattern; underlying mechanisms require further elucidation. |
MEK inhibitors: may represent a favorable subgroup. Case studies have shown clinical benefit of MEK inhibitor-based therapy in patients with advanced KRAS G12R-mutant PDAC. Pan-RAS inhibitors: potential future direction |
To be explored |
| G12C 4 |
Rare subtype (approximately 1–2%). Despite frequent CD8⁺ T cell infiltration, their function is impaired by enriched Tregs and upregulated PD-L1. |
G12C inhibitors (e.g., Sotorasib, Adagrasib): limited efficacy as monotherapy. ON/OFF-state dual inhibitors (e.g., BBO-8520): under development, may overcome resistance. Pan-RAS inhibitors: potential future direction |
High potential. Leveraging successful experience in lung cancer, clinical trials combining G12C inhibitors with immune checkpoint inhibitors (e.g., CodeBreak 101) are ongoing |
For patients with KRAS-mutant PDAC, agents directly targeting KRAS and its downstream or synergistic pathways not only exert direct cytotoxicity against tumor cells but also reverse the immunosuppressive microenvironment, thereby providing a theoretical rationale for combination immunotherapies. Conversely, KRAS wild-type (WT) PDAC lacks KRAS mutations but harbors a substantially higher proportion of potentially actionable alterations (approximately 30%), which are particularly prevalent in non-ductal histologies (67% vs. 16%). The molecular aberrations in this subtype primarily fall into two categories: alterations in RAS-associated pathway genes (such as BRAF, FGFR2, or ALK fusions) and DNA mismatch repair (MMR) deficiency [76, 77].For instance, a young patient with FGFR2 fusion-positive, KRAS WT metastatic pancreatic cancer achieved a notable and durable response exceeding 12 months with the FGFR inhibitor erdafitinib following chemotherapy failure [78].Furthermore, the AIO-PK0104 trial demonstrated that patients with KRAS WT disease exhibited significantly superior overall survival (OS) compared to those with KRAS mutations (7.9 months vs. 5.7 months), suggesting that KRAS WT status may serve as a predictive biomarker of efficacy in patients with advanced pancreatic cancer receiving erlotinib [79].Research by Ebia et al. further confirmed that among patients receiving first-line fluorouracil- or gemcitabine-based regimens, the KRAS WT cohort achieved superior therapeutic outcomes compared to the KRAS G12D/V-mutant cohort(OS: 2.1 VS 1.4 years). This study also highlighted that specific KRAS mutation subtypes are significantly associated with distinct survival outcomes [80].Therefore, comprehensive genomic profiling and fusion gene testing are imperative for the clinical management of KRAS WT PDAC.
Direct targeting of KRAS in combination with immunotherapy
Targeting KRAS G12C
The KRAS G12C mutation establishes a functionally suppressed tumor TME that is often characterized by the presence of infiltrating CD8⁺ T cells and antigen-presenting cells, yet with antitumor immunity frequently attenuated by the enrichment of Tregs and upregulation of the PD-L1 signaling axis [19]. The successful development of allele-specific KRAS G12C inhibitors has fundamentally overturned the long-standing notion of KRAS as an “undruggable” target, thereby laying a critical foundation for rational combinations with immunotherapy [81]. Currently approved or clinically advanced KRAS G12C inhibitors include sotorasib and adagrasib, among others [82].Despite these advances, the efficacy of KRAS G12C inhibitors as monotherapy in PDAC remains modest. For example, treatment with sotorasib alone achieved an ORR of only 21%, with a median PFS of 4.0 months and a median OS of 6.9 months [83]. A subsequent meta-analysis further reported an overall ORR of 25.1% for KRAS G12C inhibitor monotherapy, with median PFS and OS of 5.4 months and 8.2 months, respectively [84]. These outcomes underscore the inability of single-agent targeted therapy to overcome the highly complex and immunosuppressive TME characteristic of PDAC. Accordingly, multiple clinical trials are currently exploring combination strategies for KRAS G12C–mutant PDAC. In the CodeBreaK 101 study (NCT04185883), sotorasib is being evaluated in combination with various ICIs to assess safety and preliminary efficacy. Although detailed results for the PDAC subgroup have yet to be reported, these trials represent active and promising avenues of clinical investigation. By contrast, in non-small cell lung cancer, combinations of KRAS G12C inhibitors—such as adagrasib or olomorasib—with pembrolizumab have already demonstrated remarkable efficacy in phase II trials, with ORRs ranging from 44.3% to 70% [85, 86].Taken together, these findings highlight the urgent need for larger, PDAC-focused clinical studies to define the optimal integration of KRAS G12C–targeted therapy with immunotherapy. Such efforts may ultimately yield novel therapeutic paradigms capable of improving clinical outcomes for patients with KRAS-mutant pancreatic cancer.
Targeting KRAS G12D
KRAS G12D is the most prevalent oncogenic driver mutation in PDAC. This mutation promotes the secretion of anti-inflammatory mediators, such as TGF-β and IL-10, which not only suppress CD8⁺ T cell function but also induce epithelial-mesenchymal transition (EMT) to facilitate cancer cell migration and invasion, thereby establishing an immunosuppressive “cold tumor” microenvironment [34].From a drug development perspective, structural elucidation of the Switch II conformation of the KRAS G12D protein has provided a critical foundation for the rational design of highly selective inhibitors [87].
Currently, several KRAS G12D –targeted agents have now demonstrated substantial efficacy in both preclinical and clinical settings. For example, the novel orally available inhibitor zoldonrasib achieved partial or complete tumor regression in 77% (7/9) of pancreatic cancer mouse models [88]. In human clinical trials,,GFH375 monotherapy in previously treated patients with advanced KRAS G12D–mutant PDAC yielded a disease control rate of 97% and an ORR of 41%, highlighting its remarkable single-agent activity, which is notably superior to the ORR observed with sotorasib monotherapy (21%) [89]. The potential mechanisms underlying this discrepancy in efficacy can be analyzed from several perspectives. First, currently approved KRAS G12C inhibitors (such as sotorasib and adagrasib) selectively bind to the inactive, GDP-bound state (OFF-state) of the KRAS protein. In contrast, emerging KRAS G12D inhibitors are capable of targeting both the OFF-state and the active, GTP-bound state (ON-state). To overcome the limitations of single-state binding, direct covalent pan-state (ON/OFF) KRAS G12C inhibitors, such as BBO-8520, have recently entered clinical development [90, 91].Second, studies in colorectal cancer have demonstrated that KRAS G12C inhibitor monotherapy induces the compensatory activation of upstream receptor tyrosine kinases (RTKs), such as EGFR. This feedback loop shifts a large proportion of KRAS proteins into—or maintains them in—the ON-state, thereby diminishing the efficacy of OFF-state-restricted inhibitors and driving acquired resistance. Conversely, dual-state (ON/OFF) inhibitors like GFH375 remain unhindered by this feedback mechanism [92].Finally, KRAS G12D represents the most common and pivotal driver mutation in pancreatic cancer (accounting for approximately 40% of cases), resulting in profound oncogene addiction to its signaling pathways. In contrast, the G12C mutation is exceedingly rare in PDAC (~ 1–2%), and tumors consequently exhibit a comparatively weaker dependency on this specific alteration.
Although these results underscore the therapeutic potential of GFH375 monotherapy, achieving deeper and more durable antitumor responses will likely require rational combination strategies with immunotherapy. Compelling evidence supporting this approach was provided by Liu et al., who demonstrated that combining the KRAS G12D inhibitor MRTX1133 with a tripartite immunotherapeutic regimen targeting myeloid cells (CXCR1/2 inhibition), T cells (LAG-3 antagonism), and DCs (4-1BB agonism) resulted in durable complete responses in 36% of mice in advanced pancreatic cancer models. In contrast, all animals receiving monotherapy ultimately experienced disease progression and succumbed to tumor burden [93].These findings strongly indicate that, on the basis of potent KRAS inhibition, multidimensional immune modulation is a critical strategy for overcoming immune resistance and achieving long-term disease control in pancreatic cancer.
Pan-RAS Inhibitors
The pronounced heterogeneity of KRAS mutations in PDAC renders therapies targeting a single mutant allele particularly susceptible to the development of acquired resistance and tumor relapse [94]. Moreover, the profoundly immunosuppressive, “cold” TME characteristic of PDAC largely accounts for the limited efficacy of ICI monotherapy [11]. Against this backdrop, pan-RAS inhibitors—capable of broadly targeting multiple KRAS mutant variants, including G12D, G12C, and G12V—have emerged as a promising strategy to overcome these challenges. Notably, such agents not only exert potent direct antitumor effects but also actively remodel the TME [95, 96].Bandi et al. demonstrated that the orally available pan-RAS inhibitor ADT-1004 markedly suppressed tumor growth in preclinical models while simultaneously increasing the abundance of antitumor immune populations within the TME, including CD4⁺ and CD8⁺ T cells, M1-polarized macrophages, and dendritic cells. These findings indicate that pan-RAS inhibition has the capacity to convert immunologically “cold” tumors into “hot,” immune-inflamed phenotypes [95].Importantly, accumulating evidence suggests that durable tumor control mediated by RAS inhibition critically depends on T cell involvement, mechanistically establishing the central role of the adaptive immune system in sustaining long-term antitumor responses [97]. Building on this concept, Broderick et al. combined a multi-selective RAS(ON) inhibitor with the CDK4/6 inhibitor palbociclib, thereby synergistically inducing cell-cycle arrest in residual tumor cells. Subsequent administration of a CD40 agonist effectively reversed the immunosuppressive TME and ultimately established a state of tumor–immune equilibrium dominated by CD4⁺ T cells, resulting in durable disease control [96].
Targeting other pathways in combination with immunotherapy
Targeting PARP
Poly(ADP-ribose) polymerase (PARP) inhibitors exert antitumor activity through the induction of “synthetic lethality” and have demonstrated clear clinical efficacy in PDAC harboring homologous recombination deficiency (HRD) [21]. The phase III POLO trial established that, in patients with metastatic PDAC carrying germline BRCA mutations, maintenance therapy with the PARP inhibitor olaparib significantly prolonged median PFS (7.4 months versus 3.8 months) and reduced the risk of disease progression or death by 47% [98]. Subsequent mechanistic studies revealed that PARP inhibition can also activate the cGAS–STING signaling pathway, thereby promoting a shift of the TME toward an immune-activated state. However, this immune activation is accompanied by upregulation of PD-L1 expression, providing a strong biological rationale for combination strategies with ICIs [99]. Building on this concept, the phase II POLAR study demonstrated synergistic activity of pembrolizumab combined with olaparib in patients with HRD-mutant metastatic pancreatic cancer. In this cohort, the ORR reached 35%, with a median PFS of 8.3 months—outcomes that were markedly superior to those observed in non-classical HRD (ncHRD) tumors and platinum-sensitive subgroups. Further analyses revealed that tumors with canonical HRD exhibited higher tumor mutational burden (TMB) and increased infiltration of tumor-infiltrating lymphocytes (TILs). In the context of PDAC, where KRAS mutations are nearly ubiquitous, elevated TMB provides a rich source of neoantigens, while abundant TILs supply the effector cells necessary for antitumor immunity. Together, these features help overcome the KRAS-driven “cold tumor” phenotype, thereby establishing a strong biological foundation for combining PARP inhibitors with immune checkpoint blockade in KRAS-mutant PDAC [24].
Targeting FAK
Focal adhesion kinase (FAK) inhibitors exert immunomodulatory effects by multiple complementary mechanisms. By suppressing PD-L2 expression in stromal cells, FAK inhibition alleviates stromal-mediated T cell suppression. In parallel, FAK inhibitors promote the secretion of the chemokine CXCL10, thereby enhancing T cell trafficking and infiltration into the tumor parenchyma and collectively strengthening antitumor immune responses [100, 101]. In addition, Zhang et al. demonstrated that FAK signaling drives the formation of a dense desmoplastic barrier by cancer-associated fibroblasts (CAFs), and that pharmacological inhibition of FAK using IN10018 effectively disrupts this stromal architecture [102].Together, these findings establish FAK inhibition as a potent strategy for remodeling the immunosuppressive TME and provide a strong mechanistic rationale for its combination with immune-based therapies, including ICIs. Together, these findings establish FAK inhibition as a potent strategy for remodeling the immunosuppressive TME and provide a strong mechanistic rationale for its combination with immune-based therapies, including ICIs [103].
Targeting MEK
As a critical downstream node of oncogenic KRAS signaling, MEK represents an important therapeutic target in PDAC. Beyond its direct inhibitory effects on tumor cell proliferation, MEK inhibition can remodel the TME through multiple mechanisms, including modulation of immune cell function and suppression of immunosuppressive factor secretion, thereby providing a strong rationale for combination strategies with immunotherapy [23].
In murine PDAC models, sequential treatment with anti–PD-1/PD-L1 antibodies followed by the MEK inhibitor trametinib resulted in potent and durable tumor regression, significantly outperforming either concurrent combination therapy or monotherapy. These findings highlight the critical importance of treatment sequencing in determining therapeutic outcomes [104]. Moreover, oncogenic KRAS promotes enhanced glycolysis (the Warburg effect) and increased lactate production through activation of the RAF–MEK–ERK cascade. Accordingly, MEK inhibition can effectively reverse metabolic abnormalities in PDAC and alleviate metabolic constraints within the immunosuppressive TME [105, 106]. Although the overall efficacy of MEK inhibitor monotherapy in PDAC has been limited, emerging evidence suggests that specific molecular subtypes may derive greater benefit. For instance, in patients with advanced PDAC harboring KRAS G12R mutations, personalized MEK inhibitor therapy in later-line settings demonstrated preliminary clinical activity, with a median OS of 8.4 months and a median PFS of 4.9 months, indicating that this subtype may represent a particularly responsive population for MEK-targeted therapy [107]. More recently, in first-line treatment exploration, a phase II study evaluating the next-generation MEK inhibitor atebimetinib in combination with a modified AG regimen reported significant survival benefits (median PFS of 9.6 months and a 9-month OS rate of 86%), with a favorable safety profile. A corresponding phase III trial is currently in planning [108].
Collectively, targeted agents such as PARP inhibitors, FAK inhibitors, and MEK inhibitors not only exert direct antitumor effects through distinct molecular mechanisms but also actively remodel the immunosuppressive tumor microenvironment. Their rational combination with ICIs represents a critical frontier for overcoming immunotherapy resistance in pancreatic cancer, particularly in KRAS-mutant disease. Future research efforts should prioritize biomarker-driven patient stratification, optimization of combination regimens to maximize synergistic effects, and deeper mechanistic interrogation of resistance pathways to enable durable clinical benefit.
Local drug delivery systems
Given the complex TME of PDAC, conventional systemic chemotherapy (such as the AG regimen) is frequently hindered by severe systemic toxicities, leading to dose-limiting side effects and ultimately, treatment failure. Consequently, a variety of innovative delivery strategies have emerged in recent years. By optimizing drug accumulation and controlled release at the tumor site through diverse mechanisms, these platforms offer a rich repertoire of options for achieving high therapeutic efficacy with minimal systemic toxicity.
In terms of physical carriers, hydrogels and implantable devices effectively overcome the dense stromal barrier characteristic of PDAC. A mussel-inspired polysaccharide derivative hydrogel (OCMC-DA/CMCS-Gem@Gel) can form a localized drug depot surrounding the tumor, enabling the sustained release of gemcitabine. Studies have demonstrated that the tumor-suppressive effects and survival benefits of Gem@Gel are significantly superior to those of free gemcitabine administered either intravenously or intratumorally [109].Similarly, a nanofluidic implantable device developed by Liu et al. has shown immense potential for the localized, sustained release of CD40 antibodies, achieving equivalent tumor inhibition using only 1/4 of the standard systemic dose. This approach not only successfully circumvents systemic immune-related toxicities but also promotes the infiltration of CD8⁺ T cells and drives the repolarization of M2 to M1 macrophages within the TME. By converting PDAC from an immunosuppressive “cold” tumor to a T cell–inflamed “hot” tumor, this platform provides a safe and highly efficient delivery route for combining T cell agonists with ICIs [110].
At the nanocarrier level, integrated designs have enabled precise TME responsiveness and multi-target synergy. For example, pH-responsive magnetic mesoporous silica nanoparticles co-loaded with doxorubicin and glucose oxidase (M-MSN@DOX/Gox) achieve precise drug release within the acidic tumor microenvironment while simultaneously exacerbating intratumoral metabolic stress by catalyzing glucose consumption. Compared to free DOX, this nanosystem increased the tumor growth inhibition rate from 35% to 78% and significantly mitigated cardiotoxicity [111].Another class of membrane-camouflaged biomimetic nanoparticles (siIRAK4/Er@GEM-SS-PC-M) utilizes siIRAK4 to silence IRAK4, thereby inhibiting the NF-κB/IL-1β axis and reducing tumor stromal fibrosis, which in turn lowers the physical barriers to drug and immune cell penetration. Concurrently, this nanosystem alters the cellular uptake pathways of the drugs, effectively overcoming the pharmacological antagonism between gemcitabine and erlotinib to synergistically enhance the antitumor efficacy of chemo-targeted combination therapy. Furthermore, the hybrid membrane coating technology prolongs the in vivo circulation of the nanoparticles and improves targeting precision, enabling the synergistic triple delivery of a chemotherapeutic agent, a targeted therapy, and an antifibrotic siRNA. Notably, no significant systemic toxicities were observed in animal models, indicating an excellent biosafety profile [112].
In addition, other novel delivery strategies have demonstrated unique translational value. An oral delivery system based on probiotic spores leverages the biological tropism of the “gut-pancreas axis” to specifically deliver drugs to pancreatic tissue following intestinal absorption. This provides a potentially non-invasive, highly compliant new avenue for the localized intervention of pancreatic cancer [113].Meanwhile, micellar systems engineered with gradient-penetration capabilities can intelligently adapt to the multifaceted characteristics of the PDAC TME, enabling deep tissue penetration, on-demand drug release, and microenvironmental remodeling, thereby providing robust strategic support for precision therapy in pancreatic cancer [114].
Recent clinical trials have further corroborated the survival benefits of localized drug administration in patients. An interim analysis of the TIGeR-PaC trial, presented at AACR 2023, revealed that median overall survival (mOS) was substantially prolonged in the intra-arterial gemcitabine (IAG) group compared to the intravenous chemotherapy group (16 months vs. 10 months), representing a 60% relative extension (P = 0.051). Although this finding narrowly missed the threshold for statistical significance, the IAG regimen demonstrated promising efficacy in the treatment of locally advanced pancreatic cancer [115].The PanCO study provided further validation, showing that the implantation of ³²P microparticles combined with standard chemotherapy in patients with unresectable locally advanced pancreatic cancer achieved a 16-week local disease control rate of 90.5% and an mOS of 15.5 months (superior to 13.3 months with chemotherapy alone). Furthermore, severe adverse events related to ³²P were only 7.1%, which is profoundly lower than the 66.7% observed with chemotherapy. Notably, 23.8% of patients were successfully downstaged to resectable disease (including 8 cases of R0 resection), suggesting that combining localized radiotherapy with systemic chemotherapy can potentiate local disease control, thereby creating opportunities for curative resection in initially inoperable patients [116].
In summary, local drug delivery systems for pancreatic cancer are rapidly evolving toward greater intelligence and multifunctionality. Through strategies involving hydrogels, nanocarriers, oral spore-based systems, and advanced micellar platforms, these approaches substantially enhance local therapeutic efficacy while significantly reducing systemic toxicity. As advances in materials science continue to converge with deeper biological insights, local drug delivery systems are poised to drive pancreatic cancer treatment toward more precise, safer, and more effective therapeutic paradigms.
Biomarkers and precision therapy for KRAS-mutant pancreatic cancer
In the clinical management of pancreatic cancer, conventional serum biomarkers such as carbohydrate antigen 19 − 9 (CA19-9) and carcinoembryonic antigen (CEA) are widely used; however, their limited sensitivity and specificity have driven ongoing efforts to identify more effective biomarkers [25]. To enable precision immunotherapy for KRAS-mutant pancreatic cancer, multi-omics approaches have uncovered a growing array of promising biomarkers.At the genomic level, dynamic monitoring based on ctDNA liquid biopsy not only reflects tumor burden but also allows real-time tracking of KRAS mutation dynamics, which can serve as a powerful tool for treatment response assessment and disease monitoring [26]. In parallel, tissue-based next-generation sequencing (NGS) enables comprehensive characterization of KRAS mutation subtypes and co-mutational landscapes—such as alterations in TP53, CDKN2A, BRCA and SMAD4—thereby providing critical guidance for targeted therapies (for example, inhibitors targeting KRAS G12C or G12D) and immunotherapeutic strategies (such as PARP inhibitors for BRCA-mutant tumors) [117]. Building upon this, proteomics and exosome research offer complementary information for non-invasive diagnosis and prognostic evaluation. For instance, serum or tissue protein biomarkers identified via proteomics, such as glypican-1 (GPC1), can significantly improve diagnostic accuracy and prognostic stratification when combined with CA19-9 [25, 118].Moreover, the aberrant lipid composition in tumor-derived exosomes reflects the state of tumor metabolic reprogramming, aiding in the identification of patient subpopulations with distinct metabolic profiles [119].Furthermore, emerging insights from microbiome research have identified oral bacteria and fungi as critical risk factors for pancreatic oncogenesis. The act of swallowing is thought to facilitate the translocation of periodontal pathogens into pancreatic tissues, thereby precipitating local microecological dysbiosis. Specifically, periodontal bacteria—including Porphyromonas gingivalis, Eubacterium nodatum, and Parvimonas micra—alongside fungal species such as Candida, are associated with an elevated risk of pancreatic cancer. The interplay between these microbial kingdoms further disrupts oral microecological homeostasis. Mechanistically, prior studies suggest that Candida albicans can drive cellular proliferation through the carcinogenic metabolism of alcohol and nitrosamines, as well as via the candidalysin/macrophage IL-7 signaling axis. In parallel, P. gingivalis can migrate from the oral cavity to the pancreas, where it induces metaplasia and accelerates the progression of pancreatic intraepithelial neoplasia (PanIN) to invasive adenocarcinoma. Collectively, profiling the oral microbiota presents a promising biomarker strategy for identifying high-risk individuals, thereby offering a potential avenue for the personalized prevention of pancreatic cancer [120].( Fig. 4).
Fig. 4.
An Integrated Framework for Biomarker Stratification and Clinical Decision-Making in Precision Pancreatic Cancer Care. (Top panel) Blood-based biomarkers: This section illustrates non-invasive blood-based detection methods, including traditional serum markers (CA19-9 and CEA), circulating tumor DNA (ctDNA) for the dynamic monitoring of tumor burden and KRAS mutation status, and exosomes (carrying the GPC1 protein and aberrant lipids). The combined application of these biomarkers significantly enhances the accuracy of early detection, therapeutic efficacy monitoring, and prognostic evaluation. (Middle panel) Tissue and genomic biomarkers: This panel elucidates the core role of next-generation sequencing (NGS) of tumor tissue specimens in precision medicine. Comprehensive profiling of KRAS mutation subtypes (which guides the use of targeted inhibitors for G12D/V/R/C) and co-mutation landscapes (e.g., BRCA mutations guiding PARP inhibitor therapy) enables the integration of multi-layered biomarkers. This approach facilitates precise patient stratification and informs personalized treatment decisions. (Bottom panel) Microbiota-driven mechanisms via the oral-pancreas axis: This section reveals the potential mechanistic roles of the oral and gut microbiota in the development and progression of pancreatic cancer. Periodontal pathogens (such as Porphyromonas gingivalis and Candida albicans) can migrate via swallowing, leading to pancreatic microecological dysbiosis. The schematic details how P. gingivalis induces acinar-to-ductal metaplasia (ADM) and promotes the progression from pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma (PDAC). Additionally, it illustrates how C. albicans promotes cellular proliferation through carcinogenic metabolites and the IL-7 signaling pathway. These mechanistic insights are instrumental for identifying high-risk individuals and implementing personalized preventive strategies
However, because the aforementioned biomarkers predominantly focus on broad diagnostic and prognostic evaluation, achieving biomarker-driven precision patient stratification to guide combination immunotherapies requires the development of highly actionable, specific biomarker panels tailored to immune-reactive phenotypes:
Genomic Level: Distinct KRAS mutation subtypes shape unique immune microenvironments. Studies have shown that compared to the G12D mutation, the G12V subtype exhibits higher levels of T cell and vascular cell infiltration, alongside enhanced T cell migratory capacity. This is primarily attributed to the reduced secretion of immunosuppressive cytokines (such as GDF15, CXCL1, and IL-1ra) driven by the G12V mutation [29].Furthermore, a combined analysis of KRAS subtypes and TP53 status can stratify patients into high- and low-risk groups. The high-risk group (harboring KRAS G12D/Q61/G12V combined with a TP53 mutation) is associated with significantly shortened survival and an immunosuppressive microenvironment characterized by high PD-L1 expression and low CD8⁺ T cell infiltration. Such patients are likely to exhibit poor responses to single-agent immune checkpoint inhibitors [27].
Pathological and Spatial Omics Level: Utilizing multiplex immunohistochemistry (mIHC) or immunofluorescence (IF) technologies, the spatial distribution and activation states of critical effector cells within the tumor microenvironment (TME) can be precisely evaluated. These include CD8⁺ cytotoxic T lymphocytes, dendritic cells, M1-polarized tumor-associated macrophages, and NK cells [5].Studies reveal that the average distance between T cells and tumor cells is generally within 100 μm. In cohorts with high T cell infiltration, T cells are highly concentrated within a 15–30 μm radius of tumor cells, indicating that close spatial proximity is a critical prerequisite for T cells to exert potent antitumor effects [29].
Transcriptomic Level: RNA sequencing (RNA-seq) of tumor tissues enables the comprehensive characterization of the functional state of the TME. Key assessments include the stromal barrier (indicated by AXL expression and TGF-β signaling activity), the metabolic barrier (represented by adenosine metabolic checkpoint activity, such as CD73 expression), and antigen-presenting capacity (measured by cDC1 abundance, the formation of tertiary lymphoid structures, and the functional status of the STING signaling pathway). These transcriptomic signatures serve to guide biomarker-driven patient stratification and inform immunotherapy decision-making within the “3D + R” framework for patients with PDAC [121].
In summary, the integration of these genomic, spatial pathological, and transcriptomic features allows for the highly precise identification of patient subpopulations with potential immune reactivity. This multidimensional approach provides robust, evidence-based support for the biomarker-driven stratification of PDAC and the subsequent formulation of rational combination immunotherapy strategies.
Conclusions and future perspectives
Conclusions: This Review systematically elucidates that KRAS mutations in PDAC not only drive autonomous tumor cell proliferation but also orchestrate a profoundly immunosuppressive “cold” TME. This is achieved through multiple, interconnected mechanisms, including induction of immune cell dysfunction and exhaustion, recruitment of immunosuppressive populations such as MDSCs, establishment of a dense fibrotic stromal barrier, and metabolic reprogramming centered on enhanced glycolysis. Collectively, these processes constitute the fundamental basis for the intrinsic resistance of PDAC to immunotherapy. In response to the repeated failure of ICI monotherapy, the current research paradigm has shifted toward multimodal combination strategies. This Review summarizes the major therapeutic avenues under active investigation: combinations of immunotherapy with radiotherapy or chemotherapy leverage the “in situ vaccine” effect of radiotherapy and the immunomodulatory properties of cytotoxic agents to promote immune activation; combinations of immunotherapy with targeted therapies—including direct KRAS G12C/G12D inhibitors, PARP inhibitors, MEK inhibitors, and FAK inhibitors—aim to disrupt oncogenic signaling or cooperative pathways while simultaneously alleviating immune suppression; emerging immunotherapeutic modalities such as CAR-T cell therapy, oncolytic viruses, and CD40 agonists seek to directly activate or reprogram antitumor immune responses; and innovative local drug-delivery systems—including injectable hydrogels, stimuli-responsive nanoparticles, and oral spore-based carriers—provide critical technological support for achieving high intratumoral drug concentrations with prolonged retention and minimal systemic toxicity. Accumulating preclinical and clinical evidence indicates that rational combination strategies capable of systematically remodeling the TME are central to reversing immune tolerance and restoring effective antitumor immunity in PDAC.
Future perspectives
Future breakthroughs are likely to arise from a paradigm shift from “broad combination” approaches to “precision synergy.” A primary objective will be the development of predictive biomarker systems through the integration of ctDNA dynamics, spatial transcriptomics, proteomics, and other multi-omics technologies, enabling accurate identification of patient subgroups most likely to benefit from specific combination strategies. Such biomarker-driven stratification will be essential for implementing truly personalized immunotherapy. Building on this foundation, therapeutic strategies must evolve toward “dynamic precision intervention,” involving the development of agents or combinatorial regimens that simultaneously target KRAS signaling, stromal barriers, and metabolic reprogramming. Coupled with intelligent local delivery systems that allow spatiotemporally controlled drug release within the tumor, treatment regimens can be adaptively adjusted in response to evolving TME states to overcome therapeutic resistance. In parallel, the integration of next-generation immunotherapies—such as bispecific antibodies—with advanced delivery technologies, as well as innovations in clinical trial design incorporating immune-related biomarker endpoints, will further accelerate translational progress. Ultimately, through multidisciplinary collaboration and biomarker-guided, precision-delivery–enabled individualized combination immunotherapy, transformative immunotherapeutic strategies are poised to emerge, offering renewed hope for patients with KRAS-mutant PDA.
Author contributions
Man Li (lead): Conceptualization; data curation; methodology; investigation; writing - original draft; writing - review and editing. Xiao Wang(lead): Data curation; formal analysis. Pengen Li (lead): Conceptualization; data curation. HongJie Gong(lead): Conceptualization; investigation. Ye Mao(lead): Funding acquisition; Writing - review and editing. Jianbing Wu(lead): Conceptualization; methodology; project administration; supervision; writing - review and editing.
Funding
Project supported by the National Natural Science Foundation of China (Grant No.82160602) and Jiangxi Provincial Health Commission Science and Technology Program Project (Grant No.202410029).
Data availability
No datasets were generated or analysed during the current study.
Declarations
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
No datasets were generated or analysed during the current study.