Comprehensive Review of Immunotherapy in Colorectal Cancer: From Mechanisms to Nursing Interventions

Abstract

Colorectal cancer (CRC) is a highly prevalent malignant tumor of the digestive tract worldwide, with significant regional variations in its epidemiological characteristics. Traditional treatments including surgery, chemotherapy, and radiotherapy have limited efficacy and substantial adverse events, which can no longer meet clinical needs. In recent years, immunotherapy has brought new breakthroughs for CRC by reshaping the tumor microenvironment (TME) and blocking tumor immune escape. This review systematically summarizes the core mechanisms and clinical applications of major immunotherapies such as immune checkpoint inhibitors (ICIs) and oncolytic viruses (OVs). We focus on individualized treatment selection for different molecular subtypes (pMMR/MSS vs. dMMR/MSI-H), biomarker screening, efficacy evaluation, drug resistance mechanisms, and countermeasures. We also discuss novel targets and biomarker optimization for precision therapy. In addition, given the unique immune-related adverse events, we introduce the CRC “SSEIE” nursing model and its value in whole-process management. This review integrates the latest advances in CRC immunotherapy and nursing interventions, providing a reference for optimizing clinical regimens, improving nursing quality, and enhancing patient prognosis.

Introduction

An estimated 158,850 new cases of CRC will be diagnosed in the United States in 2026, ranking fourth among all newly diagnosed cancers nationwide.¹ Notably, recently identified favorable subsets of cancers of unknown primary (CUP), particularly the CRC‑like CUP subtype, may influence epidemiological trends. This subtype shares molecular and clinical features with CRC and is often managed using CRC treatment paradigms, which may at least partially contribute to the apparent increase in CRC incidence in recent years.² Surgery serves as the curative treatment, yet some patients are already at the middle or advanced stage at the time of diagnosis.³ Elderly patients are more prone to severe postoperative complications; however, there is no consensus that age independently affects survival outcomes. Prognosis in older patients may be confounded by tumor stage at diagnosis, tumor location, preexisting comorbidities, and treatment modality.⁴ While radiotherapy and chemotherapy can slow tumor growth, they often lack specificity, cause side effects, and face drug resistance,^5,6 necessitating new, effective treatments.

The 2026 NCCN Clinical Practice Guidelines for Colon Cancer recommend universal MMR/MSI testing for all newly diagnosed patients and prioritize immune checkpoint inhibitor therapy for those with dMMR/MSI-H colorectal cancer.⁷

Tumor immunotherapy has advanced CRC treatment by enhancing anti-tumor immunity and altering the immune environment.⁸ Immune checkpoint inhibitors have notably improved outcomes for patients with the dMMR/MSI-H subtype.⁹ Immune cell PD-L1 expression is significantly higher in dMMR/MSI-H CRC than in MMR-proficient (MSI-L) tumors, with no significant differences among different MSI-H molecular subtypes. Immunohistochemistry (IHC) and/or MSI testing are recommended for screening defective DNA mismatch repair (MMR). However, challenges remain in translating the biological and technical heterogeneity of MSI testing into clinically usable data. IHC testing of the mismatch repair system may yield inconsistent results for certain germline mutations, which may be attributed to somatic mutations.¹⁰ Optimization of strategies like immunotherapy combined with targeted therapy and dual immunotherapy,^11,12 plus exploration of biomarkers and novel targets, advances precision treatment.^13,14 However, immunotherapy causes immune-related adverse events (irAEs), which are life-threatening without timely management. Nurses play a key role in whole-course assessment and adverse event control.¹⁵ This paper reviews core advances in CRC immunotherapy, discusses irAEs management from the nursing perspective, and provides clinical references to improve patient outcomes and quality of life.

Traditional Therapies for CRC

Traditional treatments for CRC encompass surgical intervention, chemoradiotherapy, and multidisciplinary approaches.^16,17 Conventional open surgery is notably invasive;¹⁸ radical resection may leave microscopic metastases, leading to an overall recurrence and metastasis rate of 28.5%.¹⁹ Moreover, about 20% of patients are diagnosed at an advanced stage, where surgery fails to control the disease.³ Fluoropyrimidine-based chemotherapy is common: FOLFOX (5-FU, Leucovorin, and Oxaliplatin) is first-line for stage III or high-risk stage II CRC but limited by oxaliplatin’s cumulative neurotoxicity and high cost.²⁰ FOLFOX resistance in advanced CRC is associated with multiple serum miRNAs. miR‑19a differentiates resistant patients with 66.7% sensitivity and 63.9% specificity. In metastatic colorectal cancer (mCRC), treatment response to anti‑VEGF or anti‑EGFR inhibitors is associated with specific miRNA profiles: upregulation of miR‑126 correlates with bevacizumab resistance, whereas overexpression of miR‑31, miR‑100, miR‑125b and downregulation of miR‑7 are linked to cetuximab resistance, respectively.²¹ FOLFIRI (5-FU, Leucovorin, and Irinotecan) treats mCRC but is restricted by side effects and metabolite traits.²² Capecitabine suits patients intolerant to intravenous chemotherapy, with gastrointestinal reactions and bleeding risks to monitor.²³ Traditional chemotherapy yields only 11.2–15.4 months of overall survival (OS),²⁴ with notable toxicities varying by regimen. Radiotherapy for advanced tumors is limited by radiation-induced toxicities,⁶ and preventing radiation-related hematological toxicities is critical.²⁵ Due to CRC heterogeneity, traditional therapies lack universal efficacy. Immunotherapy, by activating the host immune system to target tumor antigens, boasts higher selectivity,^26,27 breaking new ground in mCRC treatment. ICIs excel in dMMR/MSI-H subtypes, achieving 31%–57% Objective Response Rate (ORR) and 73% 12-month OS with PD-1 inhibitors, balancing efficacy and safety.²⁸ Novel strategies like OVs therapy are under exploration.²⁹

Mechanisms of Immunotherapy

The core of immunotherapy is to activate or restore the body’s innate immune system, enabling it to precisely recognize and eliminate tumor cells instead of directly attacking tumors.³⁰

Immunoregulatory Properties of the CRC TME

The CRC TME consists of tumor cells, immune cells and other components, characterized by an imbalanced state dominated by immunosuppression and impaired immune activation, which forms an immune barrier via a triple network of cellular, molecular and metabolic pathways.³¹ At the cellular level, immunosuppressive cells including Myeloid-Derived Suppressor Cells (MDSCs), M2-type Tumor-Associated Macrophages (TAMs) and Regulatory T Cells (Tregs) are enriched, while effector cells such as CD8⁺ T cells and Natural Killer (NK) cells are dysfunctional.³² At the molecular level, inhibitory cytokines (Transforming Growth Factor-beta [TGF-β],³³ Interleukin-10 [IL-10]) and chemokines (eg, C-C Motif Chemokine Ligand 2 [CCL2]) form a suppressive network, and high expression of immune checkpoints including Programmed Death 1/Programmed Death Ligand 1 (PD-1/PD-L1) and Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4) blocks T cell activation. At the metabolic level, the Warburg effect, amino acid depletion and excessive Reactive Oxygen Species (ROS) further aggravate effector cell inhibition.³⁴ Consequently, the response rate of dMMR/MSI-H “hot tumors” to PD-1/PD-L1 inhibitors reaches 40%, whereas that of MSS “cold tumors” is only 0%–10%,³⁵ necessitating combination therapy to reverse immunosuppression.

Core Pathways of Immune Escape in Colorectal Cancer

MDSCs, TAMs and Tregs are key factors inducing an immunosuppressive TME, collectively promoting tumor progression and immune escape. MDSCs expand due to dysregulated bone marrow hematopoiesis,³⁶ impairing T cell function by secreting TGF-β and downregulating human leukocyte antigen class I (HLA-I), with HLA-I downregulation detected in 73% of CRC cases.³⁷ Most TAMs are M2-type, and synergize with immune checkpoint dysregulation to induce T cell exhaustion.³⁸ Tregs accumulate in the TME, suppress the responses of antigen-specific effector cells such as CD8⁺ T cells and impede tumor elimination.³⁹

Core Mechanisms and Target Applications of Immunotherapy for mCRC

The mechanisms of immunotherapy for mCRC fall into three main categories (see Figure 1): first, reversing immune escape—PD-1/PD-L1 and CTLA-4 inhibitors block their respective pathways to restore T cell function, while inhibitors of Lymphocyte Activation Gene-3 (LAG-3) and T-cell Immunoreceptor with Ig and ITIM Domains (TIGIT) are under development;⁴⁰ second, enhancing tumor recognition, which strengthens antigen presentation via antigen vaccination or promoting the maturation of Dendritic Cells (DCs);^41,42 third, activating immune cells, such as Chimeric Antigen Receptor T-cell Therapy (CAR-T)⁴³ Additionally, dMMR/MSI-H tumors feature high Tumor Mutational Burden (TMB) and abundant neoantigens,^44,45 enabling the rapid initiation of robust anti-tumor responses after immunotherapy reverses immune escape. Besides PD-1/CTLA-4 inhibitors and novel targeted agents (eg, LAG-3, TIGIT) in clinical development, OVs have opened up a new avenue for CRC immunotherapy.

Figure 1.

Core Mechanisms and Target Applications of Immunotherapy for mCRC. This schematic outlines three key strategies for mCRC immunotherapy: reversing immune evasion via PD‑1/PD‑L1, CTLA‑4/B7, and LAG‑3/MHC II pathways; enhancing tumor recognition via dendritic cell maturation; and activating immune cells using CAR‑T, cytokines, and universal antibodies to induce tumor apoptosis. In this figure, universal antibody represents PD‑1/PD‑L1 inhibitors, LAG‑3 inhibitors, and CTLA‑4 inhibitors, respectively.

Current Application and Mechanisms of OVs in Solid Tumor Therapy

OVs selectively destroy tumor cells with minor side effects. Their core functions include lysing tumor cells, inducing immunogenic cell death, disrupting tumor architecture to facilitate immune infiltration, and enhancing immune responses via the production of granulocyte-macrophage colony-stimulating factor (GM-CSF) and other factors, thus converting “cold tumors” into “hot tumors”. Multiple clinical studies on OVs have been conducted in solid tumors including CRC.⁴⁶

Clinical Application of Immunotherapy for CRC

With the accumulation of clinical evidence, immunotherapy for CRC has advanced from single-agent exploration to an era of precision and individualization, centering on drug selection, subtype matching and efficacy prediction. Rational drug use serves as the foundation, tumor molecular subtyping guides differentiated regimens as the core, and biomarker detection plus efficacy evaluation systems ensure safety and effectiveness.

Clinical Application of Immunotherapy in CRC

ICIs targeting the PD-1/PD-L1 pathway represent the core agents. PD-1 inhibitors are exemplified by pembrolizumab, nivolumab and dostarlimab, while PD-L1 inhibitors include atezolizumab, avelumab and durvalumab. Their clinical applications and supportive efficacy data are as follows:

Pembrolizumab exerts remarkable efficacy in dMMR/MSI-H patients. A Phase II trial (NCT01876511) reported a 52% ORR, 82% disease control rate (DCR), 64% 2-year OS rate in this subtype of advanced patients as second-line therapy; 11 patients with complete response remained recurrence-free for 8.3 months after treatment discontinuation.⁴⁷ The Phase III KEYNOTE-177 study established its first-line role, with median progression-free survival (PFS) (16.5 vs. 8.2 months) and ORR (45% vs. 33%) superior to standard chemotherapy combined with targeted therapy.⁴⁸ In the CheckMate 142 trial, nivolumab treated dMMR/MSI-H advanced patients with FOLFOX resistance, achieving a 31% ORR, 14.3-month median PFS and 73% 12-month OS rate, with durable benefits in some patients.⁴⁹ Its combination with low-dose CTLA-4 inhibitor ipilimumab in pretreated patients of this subtype yielded a higher 55% ORR and 85% 12-month OS rate.⁵⁰ Dostarlimab, a novel PD-1 inhibitor, showed promising results in a 2020 Phase II trial by Memorial Sloan Kettering Cancer Center (MSK): 12 stage 2–3 dMMR patients achieved complete tumor regression after neoadjuvant therapy, with 100% cure rate and no grade ≥3 adverse events during 6-month follow-up, providing a new strategy for early-stage disease.⁵¹

For PD-L1 inhibitors: single-agent atezolizumab yielded a 7.10-month median OS and 61.3% 6-month OS rate in chemotherapy-resistant mCRC patients;⁵² avelumab achieved a 24.2% ORR in dMMR/MSI-H patients and 28.6% in the MSI-H subgroup;⁵³ durvalumab treated patients with disease progression after chemotherapy, showing a 42.4% ORR, 68.3% 12-month OS rate and favorable response durability.⁵⁴

Targeted combination therapy also demonstrated efficacy. Encorafenib targets BRAF V600E-mutated protein. The Phase III BEACON trial showed that encorafenib plus cetuximab yielded an 8.4-month median overall survival (mOS) (5.4 months in the control group) and 20% confirmed objective response rate (cORR) (2% in the control group) in treated patients; the triple regimen of encorafenib, cetuximab and binimetinib further improved mOS to 9.0 months and cORR to 24%, and was FDA-approved for pretreated advanced patients with this mutation.⁵⁵

Therapeutic Regimen Selection for CRC Patients with Different Molecular Subtypes

pMMR/MSS CRC

Accounting for 85%–95% of all cases, this subtype features low TMB, weak immunogenicity and a nearly 0% ORR with PD-1 monotherapy, thus requiring combination therapy.⁵² For dual immunotherapy, durvalumab plus tremelimumab as third-line treatment for advanced patients yielded a mOS of 6.6 months (4.1 months in the control group) and a DCR of 22.7%.⁵⁶ In immunotherapy combined with targeted therapy, nivolumab plus regorafenib achieved an ORR of 33.3% and a median PFS of 7.9 months;⁵⁷ avelumab plus cetuximab resulted in an OS of 12.7 months and 14.0 months in RAS wild-type and mutant patients, respectively, offering a novel therapeutic option for this patient population.¹²

dMMR/MSI-H CRC

Accounting for 5%–15% of all cases, this subtype has high immunosensitivity.⁵⁸ PD-1 monotherapy as neoadjuvant treatment for locally advanced patients achieved a pathological complete response (pCR) rate of up to 75.9%, with an irAE incidence of only 37.5%, all of which were mild to moderate.⁵⁹ Dual immunotherapy yielded superior efficacy: the phase III CheckMate-8HW study showed that first-line nivolumab plus ipilimumab resulted in a 24-month progression-free survival rate of 72%;⁶⁰ for second-line and later therapy, the combination regimen achieved an ORR of 55% and a 1-year OS rate of 85%, outperforming monotherapy.^61,62 Treatment with PD-1 plus LAG-3 inhibitor (nivolumab plus relatlimab) in this subtype yielded an ORR of 50% and a median duration of response of 42.7 months with a median follow-up of 47.4 months, with ORR benefits observed across all subgroups.⁶³ See Table 1.

Table 1.

Therapeutic Regimens for Patients with pMMR/MSS vs. dMMR/MSI-H CRC

Molecular Subtyping of CRC	Treatment Modality	Agent	Efficacy	Reference
pMMR/MSS	Dual immunotherapy (PD-L1 inhibitor plus CTLA-4 inhibitor)	Durvalumab plus Tremelimumab	The mOS was 6.6 months, superior to 4.1 months in the best supportive care group; the DCR reached 22.7% (6.6% in the control group). One patient had a partial response (PR) lasting more than 21 months, and 21.8% of patients achieved stable disease (SD).	[56]
	Immunotherapy combined with targeted therapy (PD-1 inhibitor plus VEGFR inhibitor)	Nivolumab plus Regorafenib	The ORR was 33.3%, with 7 patients achieving sustained response; the median PFS was 7.9 months, and the 1-year PFS rate and OS rate were 41.8% and 68.0%, respectively.	[57]
	Immunotherapy combined with targeted therapy (PD-L1 inhibitor plus EGFR inhibitor)	Avelumab plus cetuximab	The OS was 12.7 months and 14.0 months for the RAS wild-type group and RAS mutant group, respectively.	[12]
	Immunotherapy combined with targeted therapy (PD-1 inhibitor plus VEGF inhibitor) in combination with fecal microbiota transplantation capsules	Tislelizumab plus Bevacizumab plus fecal microbiota transplantation (FMT)	After 6 cycles, all lesions (colon, lymph nodes, liver) were reduced with a sustained PR. A surgical resection was performed after 8 cycles, and no residual cancer cells were found in the postoperative pathology, achieving a pCR.	[65]
dMMR/MSI-H	PD-1 inhibitor	Pembrolizumab, Sintilimab, Tislelizumab, and Toripalimab were administered separately	Three patients achieved clinical complete response (CR); the ORR and pathological response rate reached 100% in the remaining 29 patients, with a major pathological response (MPR) rate of 86.2% and a pCR rate as high as 75.9%.	[59]
		Toripalimab	The pCR rate reached 65%.	[66]
		Nivolumab	The ORR was 31%, with 69% of patients achieving durable disease control for 12 weeks or longer; the median PFS was 14.3 months, the 12-month PFS rate and OS rate were 50% and 73%, respectively, and 8 patients had a duration of response exceeding 12 months.	[49]
		Dostarlimab	No tumor signs were found in all patient biopsies, with a cure rate of 100%, and no grade 3 or higher adverse events were observed.	[51]
		Pembrolizumab	The median PFS was 16.5 months, the median OS was not reached, the ORR was 45%, the median duration of response (DOR) was not reached, the incidence of grade 3 or higher treatment-related adverse events (TRAEs) was 22%, and no deaths were reported.	[67]
			The ORR was 52%; the 1-year and 2-year PFS rates were 64% and 53%, respectively; the 1-year and 2-year OS rates were 76% and 64%, respectively; the DCR (CR + PR + SD) reached 77%; among 11 patients who achieved CR and discontinued treatment for 2 years, the median treatment-free interval was 8.3 months with no recurrence observed; most TRAEs were low-grade.	[47]
			Clinical complete response (CCR) was achieved after 10 months of treatment.	[68]
	PD-L1 inhibitor	Avelumab	The ORR was 24.2% in patients with MSI-H/dMMR recurrent or advanced colorectal cancer, among whom the ORR reached 28.6% in the MSI-H subtype; the median PFS was 3.9 months and the median OS was 13.2 months.	[53]
		Durvalumab	At a median follow-up of 11.2 months, the ORR reached 42.4%, with a 12-month PFS rate of 58.2% and a 12-month OS rate of 68.3%; among the 14 responding patients, 85.7% (12 cases) remained on treatment with a stable and durable response, of whom 3 achieved a CR.	[54]
	Dual immunotherapy combination (PD-1 inhibitor plus CTLA-4 inhibitor)	Nivolumab plus Ipilimumab	The 24-month PFS rate was significantly superior to that of chemotherapy (72% vs 14%); the 24-month restricted mean survival time was prolonged by 10.6 months, and the incidence of grade 3–4 TRAEs was lower (23% vs 48%).	[60]
			Compared with nivolumab monotherapy, the combination therapy significantly improved the 1-year OS rate (85% vs 73%), ORR (55% vs 31%) and DCR for 12 weeks or longer (80% vs 69%) in patients; the PFS rates at 9 and 12 months reached 76% and 71%, with the OS rates reaching 87% and 85%, respectively. For the combination regimen, the ORR was 71% (58% in the monotherapy group), the median PFS was not reached (39.3 months in the monotherapy group), the 36-month PFS rate was 68% (51% in the monotherapy group), and the hazard ratio for disease progression was only 0.62.	[62]
			Among the 11 patients, the pCR rate reached 81.8%, with 100% of patients achieving a pathological response; the primary and metastatic lesions of one patient with liver metastasis both achieved pCR.	[69]
	Immunotherapy (PD-1 inhibitor) combined with Cyclooxygenase-2 (COX-2) inhibitor	Toripalimab plus Celecoxib	The pCR rate was 88%	[66]
	Dual immunotherapy (PD-1 inhibitor plus LAG-3 inhibitor)	Nivolumab+Relatlimab	The ORR reached 50% with a DCR of 70%; the median DOR was 42.7 months, and 96% of responders maintained response at 6 months. The median PFS was 27.5 months (3-year PFS rate: 38%), and the median OS was not reached (3-year OS rate: 56%). ORR benefits were observed across all subgroups, including age, gender, and KRAS/BRAF mutation status.	[63]
Cross-molecular subtype	Immunotherapy combined with targeted therapy and chemotherapy (PD-L1 inhibitor + VEGF inhibitor + Folinic acid, Fluorouracil, Oxaliplatin and Irinotecan (FOLFOXIRI))	Atezolizumab plus Bevacizumab plus FOLFOXIRI	It improves PFS and OS in patients with dMMR/MSI-H and pMMR/MSS subtypes of mCRC simultaneously.	[64]

In cross-subtype therapy, immunotherapy combined with targeted therapy and chemotherapy represents a key therapeutic direction for CRC (see Table 1). It significantly improves PFS and OS, exerts efficacy in both dMMR/MSI-H and pMMR/MSS patients, and further enriches the landscape of immunotherapy for CRC.⁶⁴

Biomarkers and Efficacy Evaluation of Immunotherapy

dMMR/MSI-H serves as a key predictive biomarker for the efficacy of PD-1 blockade therapy in CRC.⁷⁰ A study on 19 patients with locally advanced CRC of this subtype demonstrated characteristic changes in biomarkers in the pCR group after single-agent tislelizumab treatment: the proportions of CD8⁺T cells and CD4⁺Th cells were increased, with enhanced immune killing and response; the proportions of CD4⁺Treg cells and IL1B⁺monocytes, along with the levels of related proinflammatory factors, were decreased, achieving “resolution of inflammation” and “activation of effector immunity”.¹⁴

POLE mutations and high TMB also serve as core biomarkers for CRC immunotherapy.⁷¹ Circulating tumor DNA (ctDNA) has higher detection sensitivity for minimal residual disease in stage I-III CRC than carcinoembryonic antigen (CEA); it can act as a predictive indicator for immunotherapeutic response in patients with MSS and MSI-H subtypes. Clinical cases have confirmed its efficacy in effectively distinguishing pseudoprogression and guiding treatment adjustment.⁷² Kaplan-Meier survival analysis verified that high density of tumor-infiltrating lymphocytes (TILs) correlates with prolonged overall survival in CRC patients, enabling efficacy and prognosis assessment.⁷³ In addition, PD-L1 expression is a major predictive biomarker for ICIs response.⁷⁴ Stearoyl-CoA Desaturase 1 (SCD1) protein is highly expressed in non-T-cell inflammatory subtypes, and its clinical value as a potential biomarker is attracting increasing attention.⁷⁵

In addition to the aforementioned immunotherapy-related biomarkers, the RAS mutation status and emerging biomarkers including Human Epidermal Growth Factor Receptor 2 (HER2),⁷⁶ MET proto-oncogene, receptor tyrosine kinase (MET), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and Phosphatase and Tensin Homolog deleted on chromosome Ten (PTEN) are gradually becoming research hotspots associated with the efficacy of targeted therapy for CRC, especially anti-EGFR antibody therapy.⁷⁷

Drug Resistance Mechanisms and Corresponding Strategies for CRC Immunotherapy

MSS-type CRC exhibits an extremely low objective response rate (ORR<5%) to PD-1 inhibitor monotherapy, primarily due to the dual obstacles of a “cold tumor” phenotype and physical barriers.⁷⁸ The TME presents a “cold state” characterized by defective antigen presentation, insufficient infiltration of CD8⁺ and CD4⁺ Th1 T cells, and enrichment of immunosuppressive molecules. Dense tumor stroma further impairs drug penetration and T cell infiltration.⁷⁹ High SCD1 expression⁷⁵ and activation of the β-catenin pathway can further inhibit T cell activity and exacerbate immune resistance (see Figure 2), leading to the inefficiency of anti-PD-1 monotherapy. Therefore, it is imperative to explore combination regimens to ameliorate the TME.⁸⁰

Figure 2.

Drug Resistance Mechanisms and Corresponding Strategies for CRC Immunotherapy. This schematic depicts immune resistance in MSS-type CRC driven by the “cold tumor” phenotype and physical barriers, as well as combination strategies (eg, oncolytic viruses, bispecific antibodies) to reverse immunosuppression. Arrows indicate the direction of action, regulation, or transformation; upward arrows (↑) indicate upregulation; downward arrows (↓) indicate downregulation; ! Indicates blockade or inhibition; × indicates inhibition.

Combination therapy with OVs and PD-1/PD-L1 inhibitors can break through this bottleneck: it reverses the “cold tumor” phenotype and upregulates PD-L1 via immunogenic cell death, while degrading tumor stroma to improve penetration efficiency. OVs alone also show potential in remodeling the TME.⁸¹ Existing studies have demonstrated that Enadenotucirev monotherapy induces high CD8⁺ T cell infiltration in 80% of tumor samples; in the SPICE study combining Enadenotucirev with Nivolumab, the mOS of patients reached 16 months.⁸² Pexa-Vec combined with Durvalumab yielded a mOS of 5.2 months in chemotherapy-refractory pMMR patients (mostly MSS phenotype), offering new therapeutic potential for this refractory CRC subtype.⁸³ SCD1 inhibitors can inhibit β-catenin signaling and enhance T cell activity to exert a synergistic effect with PD-1 antibodies,⁷⁵ providing more target options for combination therapy.

T cell dysfunction and exhaustion also represent a crucial cause of immunotherapy resistance. 4–1BB costimulation is promising for ameliorating this issue, yet existing agonistic molecules suffer from drawbacks such as hepatotoxicity or insufficient activity.⁸⁴ Bispecific antibodies (BsAbs) targeting PD-1/PD-L1 and 4–1BB exhibit the advantages of low toxicity and high efficacy. As an Fc-mutated bispecific antibody, HK010 binds PD-L1 with high affinity and agonizes 4–1BB with low affinity, exerts a synergistic effect to enhance anti-tumor immunity, induces earlier complete tumor regression and elicits long-lasting immune memory. Currently, HK010 has entered clinical trials for solid tumors including CRC, thus providing a novel direction for the treatment of ICI-resistant malignancies.⁸⁵

Exploration of Novel Targets for CRC Immunotherapy

Molecular targeted drugs can directly kill tumor cells and exert immunomodulatory effects by identifying specific oncogenic targets in tumors and blocking related signaling pathways. Compared with traditional chemotherapy, these drugs have higher specificity and fewer side effects.⁸⁶ For example, regorafenib has been clinically used, and its combination with immunotherapy exerts a synergistic anti-tumor effect and improves prognosis.⁵⁷ In addition, strategies including targeting barrier to autointegration factor 1 (BANF1), administering Mn²⁺ and inhibiting the DNA damage checkpoint (ATM/Chk2 axis) can all induce anti-tumor immunity. Among them, BANF1 targeting activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway and remodels the inflammatory microenvironment. All the above strategies exert their effects by activating the cGAS-STING pathway (see Figure 3),^87,88 and the combination of BANF1-targeted therapy and immune checkpoint inhibition holds potential application value.¹³ pMMR/MSS CRC typically exhibits resistance to immune checkpoint blockade (ICB) monotherapy. A subtyping analysis involving 1424 patients identified that guanylate binding protein 2 (GBP2) is significantly expressed in patients classified as “immune-type”. GBP2 facilitates the activation of immune signaling pathways through competitive interaction with signal transducer and activator of transcription 1 (STAT1). This interaction enhances the machinery for tumor antigen processing and presentation (APM) and promotes the recruitment of CD8⁺ T cells via CXCL10/11, thereby augmenting the immune microenvironment. Both in vitro and in vivo studies have demonstrated that elevated GBP2 expression can enhance the responsiveness of these tumors to PD-1 inhibitors, suggesting that GBP2 represents a promising novel target for combination ICB therapy.⁸⁹

Figure 3.

This schematic depicts the immune regulatory network and precision therapeutic targets in the colorectal cancer tumor microenvironment, including both established and emerging immunotherapy and targeted therapy targets. It further integrates the SSEIE nursing intervention module, which centers on full-cycle precision management for irAEs. The figure illustrates the synergistic relationship between systemic anti-tumor therapies and specialized nursing care. Arrows indicate the labeling and targeting of immune cells toward tumor cells.

Individualized Therapy and Biomarker Optimization

Conventional therapies show limited efficacy in patients with special phenotypes of mCRC, making biomarker-guided personalized medicine combined with individual patient characteristics increasingly important.⁹⁰ However, tumor-agnostic biomarkers face major challenges in clinical implementation. Non-standardized molecular testing results in inconsistent detection and interpretation. Tumor heterogeneity and adaptive resistance, such as bypass signaling in BRAF-mutant CRC, hinder durable treatment strategies. Moreover, high costs and unequal access to genomic profiling limit their real-world applicability.⁹¹ In addition to medical history, genomic profiles (eg, dMMR/MSI-H, POLE mutation), TMB and specific antigens such as Carcinoembryonic Antigen-Related Cell Adhesion Molecule 5 (CEACAM5) have become key bases for treatment decision-making. Assessing patients’ molecular characteristics and target expression enables the identification of therapeutic response potential, optimization of clinical decisions, and realization of precision therapy.

Biomarker-driven personalized therapy has demonstrated definite clinical value: a 40-year-old patient with stage III mCRC carrying MSI-H, POLE mutation and high tumor burden achieved CR after 42 days of stepwise therapy, with a PFS of 21 months by March 2024;⁹² Precem-TcT, a CEACAM5 antibody-drug conjugate (ADC), was administered to 40 irinotecan-resistant patients at an individualized dose of ≥2.4 mg/kg, yielding a median PFS of 6.7 months and a DCR of 58.8%;⁹³ GCC19/CD19 dual-target CAR-T therapy was used in 15 patients with multi-line treatment failure, with 40% achieving PR; the high-dose group had a median PFS of 6.0 months and OS of 22.8 months, with manageable toxicities.⁹⁴ For patients with BRAF V600E mutation, the encorafenib + cetuximab regimen shows significant efficacy but is associated with adverse events, and nursing staff ensure treatment benefits through early identification, precise intervention, medication education, remote monitoring and psychological support.⁹⁵

In the future, personalized therapy for mCRC will further advance biomarker application and explore novel therapeutic strategies, which places higher demands on clinical nursing. It is necessary to synchronously focus on individualized monitoring of patients’ molecular characteristics, regimen adjustment and adverse reactions, so as to provide full-course support for precision therapy.

The above mechanistic and clinical advances collectively highlight the central role of safe, patient-centered care in realizing the full benefits of immunotherapy. As such, a unified framework that integrates mechanisms, clinical strategies, and specialized nursing is essential to optimize outcomes for patients with CRC.

The occurrence and management of irAEs serve as a critical bridge linking the mechanistic basis of immunotherapy to patient clinical outcomes. Although the immune mechanisms and clinical manifestations of irAEs have been increasingly characterized, effective control in real‑world practice requires far more than isolated medical intervention. Given the systemic and heterogeneous nature of irAEs, a coordinated multidisciplinary strategy is essential to ensure early recognition, accurate grading, and timely intervention. This integrated model unifies scientific understanding and clinical implementation, and establishes a structured framework in which nursing can assume a central and well‑defined role.

The “SSEIE” Nursing Model for CRC

While immunotherapy provides survival benefits for patients with CRC, irAEs present substantial systemic challenges to clinical nursing owing to their heterogeneity, occult onset, and high incidence in the intestine. Nurses should establish a full‑cycle standardized nursing system to guarantee treatment safety and continuity.

Pre-treatment care centers on risk prevention and control: integrate patients’ baseline immune function, comorbidities and prior treatment history to develop a standardized irAEs risk screening scale for accurately identifying high-risk individuals. Nurses conduct comprehensive risk stratification in collaboration with the oncology medical team, and pharmacists provide professional advice on medication safety and potential risks. The mechanism of ICIs is popularized via verbal and graphic education to clarify irAEs characteristics. With the MASCC Oral Agent Teaching Tool (MOATT), patients are guided to recognize early warning symptoms of intestinal irAEs, enhancing their self-management awareness and treatment adherence.⁹⁶

Intra-treatment care focuses on dynamic monitoring and graded intervention of irAEs. In accordance with the ESMO 2022 Guidelines,⁹⁷ a tripartite assessment of symptom inquiry, laboratory indicators and specialist physical signs is conducted, with key monitoring of high-incidence sites such as intestine and liver. A monitoring network of outpatient care, remote follow-up and digital tools is established; real-time home-based symptom feedback is achieved via electronic patient-reported outcome (ePROs) platforms (eg, V-Care),⁹⁸ medication administration and infusion reaction monitoring are standardized,⁹⁹ forming a closed-loop management. For mild toxicities, symptomatic nursing is provided (eg, low-residue diet guidance for intestinal irAEs); for moderate-to-severe toxicities, multidisciplinary team (MDT) consultation including oncologists, pharmacists, and organ specialists is activated. Pharmacists provide professional support in drug adjustment and safety monitoring, while nurses coordinate the whole team for timely intervention.

Post-treatment nursing follow-up is extended to 1–2 years: delayed irAEs are monitored through reexaminations and remote follow-up,¹⁰⁰ long-term toxicity data are collected, and cross-setting rehabilitation guidance of “hospital-community-family” is promoted.¹⁰¹ Meanwhile, nursing effects and existing problems are evaluated, professional training of nursing staff¹⁰² and the application of digital tools are strengthened, forming a continuous improvement cycle of “practice-assessment-optimization”.

The above measures cover five core dimensions of “Screening-Surveillance-Education-Intervention-Evaluation”, thus constructing the “SSEIE Nursing Model” (see Figure 4). Centered on full-cycle precise management, this model integrates immunological mechanisms, clinical treatment, and specialized nursing closely, providing a standardized and replicable practice system for CRC irAEs nursing, improving nursing quality and patient benefits. This SSEIE model is not only a comprehensive nursing protocol but also a cohesive extension of the mechanistic and clinical discussions, ensuring that nursing practice is fully aligned with scientific rationale and real-world clinical demands.

Figure 4.

The SSEIE Nursing Model. This schematic illustrates the full-cycle SSEIE nursing model for adverse events in colorectal cancer immunotherapy, encompassing five core dimensions: risk screening, active surveillance, health education, graded intervention, and outcome evaluation, forming a closed-loop management system.

Conclusions

The treatment of CRC has evolved from traditional tumor-killing strategies to precision therapies targeting the TME. Conventional radiotherapy and chemotherapy are restricted by local efficacy, systemic toxicity, and drug resistance, whereas immunotherapy offers durable responses and mild adverse effects, especially for dMMR/MSI-H subtype CRC. Management of irAEs is critical for safe and effective treatment; nurses should implement early intervention through baseline assessment, dynamic monitoring, and signal recognition to improve treatment tolerance and quality of life.

This review integrates mechanistic insights, clinical advances, and evidence‑based nursing into a coherent whole, offering a comprehensive and in‑depth understanding of immunotherapy for colorectal cancer.

With further mechanistic research, novel drug development, regimen optimization, and integration of biomarkers, multidisciplinary collaboration, and individualized nursing, CRC immunotherapy will benefit more patients and achieve the goal of maximizing efficacy while minimizing risks.

Funding Statement

This work was supported by the Natural Science Foundation of Jilin Provincial Department of Science and Technology (Grant No. YDZJ202501ZYTS804, Principal Investigator: MYK).

Clinical Trial Registration

Clinical trial number: not applicable. This is a review article that does not involve clinical trials or patient-level data collection; therefore, no clinical trial registration is required.

Abbreviations

APM, Antigen Processing and Presentation Machinery; BANF1, Barrier to Autointegration Factor 1; CAR-T, Chimeric Antigen Receptor T-cell Therapy; CCL2, C-C Motif Chemokine Ligand 2; CEACAM5, Carcinoembryonic Antigen-Related Cell Adhesion Molecule 5; cGAS-STING, Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes; cORR, Confirmed Objective Response Rate; CR, Complete Response; CRC, Colorectal cancer; ctDNA, Circulating tumor DNA; CTLA-4, Cytotoxic T-Lymphocyte-Associated Protein 4; DCR, Disease Control Rate; DCs, Dendritic Cells; dMMR/MSI-H, Deficient Mismatch Repair/Microsatellite Instability-High; EGFR, Epidermal Growth Factor Receptor; GBP2, Guanylate Binding Protein 2; GM-CSF, Granulocyte-Macrophage Colony-Stimulating Factor; HER2, Human Epidermal Growth Factor Receptor 2; HLA-I, Human Leukocyte Antigen Class I; ICB, Immune Checkpoint Blockade; ICIs, Immune Checkpoint Inhibitors; IL-10, Interleukin-10; irAEs, Immune-related Adverse Events; LAG-3, Lymphocyte Activation Gene-3; mCRC, Metastatic Colorectal Cancer; MDSCs, Myeloid-Derived Suppressor Cells; MET, MET proto-oncogene, receptor tyrosine kinase; mOS, Median Overall Survival; MPR, Major Pathological Response; NK, Natural Killer Cell; ORR, Objective Response Rate; OS, Overall Survival; OVs, Oncolytic Viruses; pCR, Pathological Complete Response; PD-1/PD-L1, Programmed Death 1/Programmed Death Ligand 1; PFS, Progression-Free Survival; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PMMR/MSS, Proficient Mismatch Repair Microsatellite Stable; PR, Partial Response; PTEN, Phosphatase and Tensin Homolog deleted on chromosome Ten; ROS, Reactive Oxygen Species; SCD1, Stearoyl-CoA Desaturase 1; STAT1, Transducer and Activator of Transcription 1; TAMs, Tumor-Associated Macrophages; TGF-β, Transforming Growth Factor-beta; TIGIT, T-cell Immunoreceptor with Ig and ITIM Domains; TILs, Tumor-Infiltrating Lymphocytes; TMB, Tumor Mutational Burden; TME, tumor microenvironment; Tregs, Regulatory T Cells; VEGF, Vascular Endothelial Growth Factor.

Data Sharing Statement

Data sharing is not applicable to this article as no data were created or analysed in this study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agreed to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.