The mechanism and research progress of PD-1/PD-L1 on immune escape of lung cancer

Abstract

According to the latest Global Cancer Observatory (GLOBOCAN) 2022 estimates, lung cancer remains the second most commonly diagnosed cancer worldwide, with approximately 2.48 million new cases (11.4% of all cancer diagnoses) and over 1.86 million deaths (18.2% of all cancer-related deaths), making it the leading cause of cancer mortality globally. It has been reported that programmed death ligand 1 (PD-L1) is confirmed to interact with the tumor microenvironment (TME) to mediate the immune escape of lung cancer. PD-L1, which is highly expressed in lung cancer cells, activates the programmed death receptor 1 (PD-1)/PD-L1 signaling pathway by binding to PD-1, thereby inhibiting the function of lymphocytes and the release of cytokines, inducing activated lymphocyte apoptosis, resisting the killing effect of lymphocytes, ultimately leading to immune escape in lung cancer. PD-L1 inhibitors, a hot spot in tumor immunotherapy, can restore the activity of T cells, thereby enhancing the body’s immune response, and ultimately enabling the immune system to effectively recognize and kill lung cancer cells, thereby enabling lung cancer patients to achieve long-term tumor remission. At present, a variety of PD-L1 inhibitors have been approved for application and have achieved good clinical efficacy in the treatment of lung cancer. This article reviews the research progress of the interaction between PD-L1 and the TME to mediate immune escape from lung cancer and the role of PD-L1 inhibitors in the treatment of lung cancer.

Introduction

Lung cancer is one of the common malignant tumors worldwide, with high metastasis rate and recurrence rate. Despite advances in treatment, the 5-year survival rate for lung cancer remains below 20%, largely due to late-stage diagnosis and high metastatic potential (1). Although targeted therapies offer specificity and fewer side effects, their efficacy can be compromised by gene mutations and drug resistance. Immunotherapy, particularly monoclonal antibodies such as programmed death receptor-1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors, represents a distinct treatment modality. While the initial cost of these agents was high, recent years have seen a reduction in price due to the availability of biosimilars and commercial agreements, improving accessibility for broader patient populations (2). With the development of immunology and molecular biology, immunotherapy has become a research hotspot. PD-1, first identified by Ishida et al. in 1992, and its ligand PD-L1 are negative immunomodulatory molecules that have attracted increasing attention in recent years due to their crucial role in the immune escape mechanism of tumor cells (3). The activation of PD-1/PD-L1 signaling can lead to the formation of immunosuppressive tumor microenvironment (TME), which enables tumor cells to evade the monitoring and killing of the immune system (4).

At present, the core of tumor immunotherapy is to activate the anti-tumor effect of T lymphocytes and improve the killing ability of tumor cells. A recent study has found that PD-L1 is highly expressed in a variety of tumors and inhibits the proliferation and activation of lymphocytes and anti-tumor immunity by binding to PD-1 molecules on the surface of tumor-infiltrating lymphocytes (TILs), which is one of the important reasons for tumor immune escape (5). Therefore, it is of great clinical significance to study the mechanism of PD-1/PD-L1 signaling in tumor immune escape and provide reliable evidence and ideas for tumor immunotherapy. This review summarizes and analyzes the mechanism and research progress of PD-1/PD-L1 in tumor immune escape. This article is presented as a narrative review, aiming to integrate key clinical trial results, molecular mechanisms, and evolving therapeutic strategies related to PD-1/PD-L1 inhibitors in lung cancer. A narrative format was chosen to provide both a broad perspective and an in-depth interpretation of rapidly developing areas that may not yet be captured in systematic analyses.

Molecular mechanism of PD-1/PD-L1 on tumor immune escape of lung cancer

PD-1 is a transmembrane receptor on T cells, which is named programmed death 1 receptor because it is involved in the process of cell apoptosis (3). PD-1 is a transmembrane glycoprotein of approximately 55 KDa encoded by the PDCD1 gene located on chromosome 2Q37.35. PD-1 is mainly expressed on the membrane surface of T cells, B cells, natural killer (NK) cells, and a variety of tumor cells (6). It has been confirmed that the ligands of PD-1 are composed of PD-L1 and PD-L2, both of which belong to the B7 superfamily, and the coding genes are located on human chromosome 9P24.2. PD-L1 (also known as B7-H1, CD274) is the main ligand of PD-1, which is widely expressed on the surface of antigen presenting cells (APCs), macrophages, activated T cells and B cells, monocytes, and endothelial cells (7). However, the expression of PD-L2 (also known as B7-DC and CD273) was limited, mainly expressed in macrophages, dendritic cells (DCs), and mast cells.

PD-1 binds to PD-L1 and induces tyrosine phosphorylation of the immunoreceptor tyrosine-based switch motif (ITSM) in the intracellular region of PD-1 mainly through T cell receptor (TCR) signaling, which then recruits protein tyrosine phosphatase 1 (SHP-1) and protein tyrosine phosphatase 2 (SHP-2) in the Src homeodomain (8). SHP-2 dephosphorylates TCR-associated CD3ζ and Zeta chain-associated protein kinases (ZAP70), thereby inhibiting T-cell activation signals, including phosphoinositide 3-kinase (PI3K) and its downstream protein kinase Akt, glucose metabolism disorders, and interleukin-2 secretion inhibition (9). The negative signal mediated by this process can effectively block the proliferation and activation of T lymphocytes and the secretion of cytokines, and negatively regulate the immune response (10). The activated T cells show a state of “hyper exhaustion”, which reduces the activity of effector T cells and terminates the immune response. Under normal circumstances, excessive inflammatory reaction or autoimmune reaction can be prevented (11). The significant expression of PD-L1 on the surface of lung cancer cells and its binding to PD-1 on the surface of lymphocytes will weaken the body’s anti-tumor immune function, form an immune microenvironment conducive to tumor survival, promote tumor immune escape, and participate in the occurrence and development of tumors (12,13) (Figure 1). Recent studies have shown that both PD-1/PD-L1 can participate in tumor immune escape through a variety of molecular signaling pathways (14-17).

Figure 1.

Mechanism of action of PD-1/PD-L1 inhibitors. APC, antigen-presenting cells; MHC, major histocompatibility complex; PD-1, programmed death receptor 1; PD-L1, programmed death ligand 1; TCR, T cell receptor.

Hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) signaling pathways

Hypoxia is a common feature of the TME in lung cancer, contributing significantly to immune escape and therapeutic resistance. Under hypoxic conditions, the transcription factor HIF-1α is stabilized and translocated into the nucleus, where it binds to hypoxia response elements (HREs) in the promoter region of several target genes, including PD-L1 (18). This leads to the upregulation of PD-L1 expression in tumor cells, thereby enhancing their ability to evade cytotoxic T lymphocyte (CTL) surveillance by engaging the PD-1 receptor and inducing CTL apoptosis or exhaustion (19).

In addition to PD-L1, HIF-1α also promotes the transcription of VEGF, a key driver of tumor angiogenesis (18). VEGF not only facilitates neovascularization but also plays a pivotal role in shaping an immunosuppressive microenvironment. Elevated VEGF levels inhibit DC maturation, impair antigen presentation, promote the recruitment of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and reduce the infiltration and activation of effector T cells in tumor tissue (19,20). These effects collectively result in an immunologically “cold” TME, which is typically less responsive to immune checkpoint inhibitors such as anti-PD-1/PD-L1 antibodies.

Moreover, clinical studies have suggested that patients with tumors exhibiting high HIF-1α or VEGF expression may display primary resistance to PD-1/PD-L1 blockade. To address this, combination strategies involving anti-VEGF agents (e.g., bevacizumab) and PD-1/PD-L1 inhibitors (e.g., atezolizumab) have been developed and shown to improve therapeutic outcomes by simultaneously normalizing the vasculature and restoring T cell infiltration (18,20). Thus, the HIF-1α-VEGF axis plays a central role in mediating tumor immune escape and influencing the sensitivity or resistance to PD-1/PD-L1-targeted immunotherapy (Figure 2).

Figure 2.

Hypoxia-induced regulation of PD-L1 expression and immune evasion via the HIF-1α/VEGF pathway. CTL, cytotoxic T lymphocyte; DC, dendritic cell; HIF-1α, hypoxia inducible factor-1α; MDSC, myeloid-derived suppressor cell; PD-1, programmed death receptor 1; PD-L1, programmed death ligand 1; Treg, regulatory T cell; VEGF, vascular endothelial growth factor.

Tumor-derived transforming growth factor-β (TGF-β) signaling pathway

TGF-β is a multifunctional cytokine with potent immunosuppressive properties, playing a key role in promoting immune tolerance and tumor immune escape. Within the TME, TGF-β is secreted by tumor-associated DCs, cancer cells, and Tregs, and contributes to immunosuppression through several mechanisms (20).

One key pathway involves the suppression of effector T cell function via transcriptional reprogramming. TGF-β inhibits the expression of special AT-rich binding protein 1 (SATB1), a chromatin organizer that normally acts to repress PD-1 transcription in activated T cells (21). Specifically, TGF-β activates SMAD signaling cascades that bind to the SATB1 promoter and inhibit its expression, thereby preventing SATB1 from recruiting the NuRD histone deacetylase complex to PD-1 enhancer regions (22). This epigenetic derepression leads to upregulated PD-1 expression, promoting T cell exhaustion and loss of cytotoxic function in the TME.

In addition, TGF-β exerts physical barriers to immune infiltration by inducing stromal remodeling and extracellular matrix deposition. This leads to the formation of the so-called “immune-excluded phenotype”, in which CD8⁺ T cells are trapped in the stromal periphery and fail to infiltrate the tumor core. Such tumors typically exhibit poor responses to PD-1/PD-L1 inhibitors, not due to lack of antigenicity, but due to spatial segregation of immune effectors from target cells.

To overcome this form of resistance, a recent preclinical and clinical study has evaluated dual blockade of TGF-β and PD-L1, including fusion proteins such as SHR-1701, which simultaneously targets the PD-L1 and TGF-β pathways (20). These strategies have shown promise in reversing T cell exclusion and enhancing the efficacy of immune checkpoint blockade. Overall, TGF-β-driven immune exclusion and PD-1 upregulation represent major mechanisms of adaptive immune resistance, and targeting this axis may significantly improve patient response to immunotherapy (Figure 3).

Figure 3.

TGF-β signaling promotes PD-1 expression and immune exclusion. GSK-3β, glycogen synthase kinase 3 beta; PD-1, programmed death receptor 1; PD-L1, programmed death ligand 1; TGF-β, transforming growth factor-β.

Glycogen synthase kinase-3 (GSK-3) signaling pathway

GSK-3 is a constitutively active serine/threonine kinase involved in diverse cellular functions, including metabolism, cell cycle regulation, and immune modulation. In the context of T cell immunity, GSK-3 plays a critical role in regulating PD-1 expression and T cell exhaustion. Upon TCR activation, GSK-3 is transiently inhibited, which permits the transcriptional upregulation of T-bet (T-box transcription factor TBX21), a key transcriptional repressor of PD-1 (PDCD1) (23,24).

T-bet directly binds to the promoter region of PDCD1 and suppresses its transcription, thus maintaining effector T cell function and preventing exhaustion. However, in TILs, chronic antigen stimulation and aberrant TME signals can restore GSK-3 activity, which suppresses T-bet levels and thereby sustains PD-1 expression. This shift leads to a progressive loss of T cell cytotoxicity, cytokine secretion, and proliferation capacity—a hallmark of exhausted T cells (24).

Experimental inhibition of GSK-3 using small molecule inhibitors or siRNAs has been shown to restore T cell function by reducing PD-1 expression and enhancing interferon-gamma (IFN-γ) and granzyme B production in CD8⁺ CTLs. Importantly, Taylor et al. confirmed that GSK-3 inactivation increases the binding affinity of T-bet to the PDCD1 promoter, further validating the regulatory axis (24). In in vivo tumor models, pharmacological GSK-3 inhibition synergized with PD-1 blockade to improve antitumor efficacy, suggesting that GSK-3 inhibition can act as a sensitizer to immune checkpoint therapy (25).

Thus, GSK-3 represents a critical upstream regulator of PD-1 expression and T cell exhaustion, and targeting this pathway offers a promising strategy to reverse resistance and enhance the clinical efficacy of PD-1/PD-L1 inhibitors (Figure 4).

Figure 4.

GSK-3-T-bet-PD-1 axis regulates T cell exhaustion and checkpoint sensitivity. CTL, cytotoxic T lymphocyte; GSK-3, glycogen synthase kinase-3; HIF-1α, hypoxia inducible factor-1α; MDSC, myeloid-derived suppressor cell; PD-1, programmed death receptor 1; PD-L1, programmed death ligand 1; Treg, regulatory T cell; VEGF, vascular endothelial growth factor.

Application of PD-1/PD-L1 inhibitors in lung cancer

Table 1 shows the clinical treatment and indications of PD-1/PD-L1 inhibitors widely used in advanced lung cancer in China and other countries.

Table 1. The clinical treatment and indications of PD-1/PD-L1 inhibitors used in advanced lung cancer.

Drug name	Target	R&D institutions	Antibody type	Pivotal trial	Global clinical trials	Chinese clinical trials	Approved	Other major approved indications
Nivolumab	PD-1	Ono Pharmaceutical	IgG4	CheckMate-017, CheckMate-057	75	7	US [2014], China [2018]	Metastatic melanoma, adjuvant melanoma therapy, metastatic non-small cell lung cancer, classical Hodgkin lymphoma, renal cell carcinoma, head and neck squamous cell carcinoma, hepatocellular carcinoma, urethral carcinoma, bladder cancer, mismatch repair deficiency colon cancer
Pembrolizumab	PD-1	Merck	IgG4	KEYNOTE-024, KEYNOTE-042, KEYNOTE-010	103	15	US [2017], China [2018]	High microsatellite unstable tumors, melanoma, non-small cell lung cancer, classic Hodgkin lymphoma, head and neck squamous cell carcinoma, urethral cancer, gastric cancer
Atezolizumab	PD-L1	Roche	IgG1	IMpower-110, IMpower-010	51	6	US [2016], China [2019]	Advanced bladder cancer, locally advanced or metastatic urethral cancer, Metastatic non-small cell lung cancer, locally advanced or metastatic urethral cancer

IgG, immunoglobulin G; PD-1, programmed death receptor 1; PD-L1, programmed death ligand 1; R&D, research and development.

Nivolumab

Nivolumab is a human immunoglobulin (IgG4) anti-PD-1 monoclonal targeted drug approved by the US Food and Drug Administration (FDA) for the treatment of lung cancer, which is mainly used for single chemotherapy or combined with other chemotherapy drugs (26). However, nivolumab is no longer considered a primary option in first-line therapy for non-small cell lung cancer (NSCLC). Recent treatment guidelines now favor pembrolizumab and atezolizumab as first-line agents, either as monotherapy or in combination with chemotherapy, based on PD-L1 expression levels and tumor histology. Nivolumab is currently available as a second-line treatment for advanced lung cancer after the failure of standard platinum-based first-line chemotherapy. A phase I clinical study evaluated the efficacy and safety of nivolumab in 296 patients with advanced solid tumors, and the results showed that the objective response rate (ORR) of nivolumab-treated NSCLC patients was 17.1%, 1-, 2- and 3-year survival rates were 42%, 24%, and 18%, respectively (26). Horn et al. randomized 582 patients to nivolumab or docetaxel group, and results showed that overall survival (OS) was improved with nivolumab compared with docetaxel, with an OS of 12.2 months in the nivolumab group and 9.4 months in the docetaxel group (27). Brahmer et al. randomly selected 272 patients with lung squamous cell carcinomas (LUSC) who failed platinum-based first-line chemotherapy and divided them into two groups: one group received nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks, and the other one received docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks. Results showed that compared with docetaxel, median survival was longer with nivolumab (9.2 vs. 6 months) and a higher ORR (20% vs. 9%). In terms of safety, nivolumab had fewer grade 3 or 4 chemotherapy-related adverse events than docetaxel (7% vs. 55%) (28). Based on the data from the above clinical studies, in March 2015, the FDA approved nivolumab for the use of platinum-containing doublet chemotherapy in patients with LUSC, and in October of the same year, it was approved for the second-line treatment of non-squamous NSCLC. As such, nivolumab’s role in lung cancer has become more historically relevant or confined to second-line settings. For a detailed overview of current first-line immunotherapy strategies, including KEYNOTE-189 and IMpower110.

Pembrolizumab

Pembrolizumab, a monoclonal antibody to human immunoglobulin (IgG4) against PD-1, is used as first-line therapy for advanced lung cancer with PD-L1 expression ≥50% and second-line therapy for PD-L1 expression ≥1%. In addition to its use in monotherapy settings, pembrolizumab has been established as a standard first-line treatment in combination with chemotherapy, based on two landmark clinical trials: KEYNOTE-189 for non-squamous NSCLC and KEYNOTE-407 for squamous NSCLC. A total of 495 patients with advanced lung cancer were included in the pembrolizumab phase I clinical study, and ultimately, both the initial and retreatment patients could achieve an effective response rate (24.8% vs. 18.0%) (29). Herbst et al. randomly assigned 1,034 patients with NSCLC (all histological types) and PD-L1 expression of at least 1% to pembrolizumab or docetaxel. The results showed that patients in the two groups who received pembrolizumab had better survival, with OS of 10.4 and 12.7 months, respectively, compared with 8.5 months for docetaxel. Moreover, patients with PD-L1 expression higher than 50% had an OS of 17.3 months, suggesting a correlation between PD-L1 expression and the efficacy of pembrolizumab (30). In KEYNOTE-189, the combination of pembrolizumab with pemetrexed and platinum chemotherapy significantly improved OS [22.0 vs. 10.7 months; hazard ratio (HR), 0.49; P<0.001] in patients with non-squamous NSCLC regardless of PD-L1 status (31). Similarly, the KEYNOTE-407 trial showed survival benefit in patients with squamous NSCLC treated with pembrolizumab plus chemotherapy (15.9 vs. 11.3 months; HR, 0.64; P=0.001) (32). Reck et al. presented the results of the phase III KEYNOTE 024 study at the European Society of Oncology Congress, which showed that pembrolizumab was more effective than platinum-based chemotherapy in the initial treatment of advanced NSCLC with high PD-L1 expression (>50%). A total of 305 patients were randomly assigned 1:1 to pembrolizumab and chemotherapy, and results revealed that the progression-free survival (PFS) of pembrolizumab and chemotherapy were 10.3 and 6.0 months, respectively, and the ORR of pembrolizumab and chemotherapy were 45% and 8%, respectively, with fewer adverse events than chemotherapy (27% vs. 53%) (33). The 2017 National Comprehensive Cancer Network (NCCN) guidelines mention first-line use of pembrolizumab in patients with PD-L1 expression greater than 50% and no driver mutations (34). More recently, KEYNOTE-671 demonstrated that perioperative pembrolizumab (neoadjuvant plus adjuvant) significantly improved event-free survival and pathological complete response in patients with resectable stage II–IIIB NSCLC, suggesting its utility even in early-stage disease (35).

Atezolizumab

Atezolizumab, a monoclonal antibody targeting programmed death ligand (PD-L1 or CD274 antigen), was developed by Genentech for the treatment of various hematological malignancies and solid tumors. It has been approved as a second-line treatment for transitional cell carcinoma in the United States and is undergoing clinical trials as a second-line treatment for cell lung cancer. In a phase I study to evaluate atezolizumab monotherapy in patients with different types of advanced tumors, 53 patients in the NSCLC group were evaluable, with a response rate of 23% and a median PFS of 15 weeks. Mazieres et al. conducted an open randomized controlled trial of patients with advanced lung cancer who had progressed after first-line chemotherapy, in which 287 patients were enrolled in a random group to receive atezolizumab or docetaxel. Results showed that the OS was longer in the atezolizumab group than in the docetaxel group (12.6 vs. 9.7 months), indicating that atezolizumab significantly improved OS in the total population (36). In the IMpower110 trial, atezolizumab was evaluated as a first-line monotherapy in patients with stage IV NSCLC expressing PD-L1 on ≥1% of tumor cells or immune cells. In patients with high PD-L1 expression (TC3 or IC3), atezolizumab significantly prolonged OS compared to chemotherapy, with a median OS of 20.2 vs. 13.1 months (HR, 0.59; 95% confidence interval: 0.40–0.89; P=0.01) (37). This study led to the approval of atezolizumab as a first-line option in PD-L1-high patients, particularly those not suitable for combination chemo-immunotherapy regimens.

Adverse reactions of PD-1/PD-L1 inhibitors in lung cancer

Immune checkpoint inhibitors prevent tumor immune escape and enhance the body’s anti-tumor effect by blocking the negative regulatory signals of T cells, but at the same time, they can also enhance the normal immune response of the body, resulting in excessive activation of the immune system and triggering an autoimmune response, that is, the immune-related adverse events (irAEs) (38). Among endocrine-related irAEs, thyroid dysfunction—particularly thyroiditis and hypothyroidism—is one of the most common, occurring in approximately 10–20% of patients. Thyroiditis often begins as transient hyperthyroidism and progresses to hypothyroidism, which may require long-term thyroid hormone replacement therapy. Routine monitoring of thyroid function during immunotherapy is recommended to enable early detection and intervention. With the wide application of immune checkpoint inhibitors, irAEs are also increasing, which often occur in the early stage after the start of treatment. The most common adverse reactions include skin diseases, gastrointestinal tract, endocrine, and pulmonary, cardiovascular, kidney or nervous system, etc. (39). A study has shown that only 5% of lung cancer patients who received anti-PD-1/PD-L1 immunotherapy in phase I clinical studies had irAEs, including fatigue, gastrointestinal discomfort, and skin reactions, among which grade 3–4 irAEs accounted for 14% (40). Later phase II clinical trials (CheckMate 063) and large randomized phase III controlled studies (CheckMate 017) found similar AEs: fatigue, anorexia, nausea, asthenia, rash, diarrhea, etc.; the most common grade 3–4 AEs were mainly fatigue, anorexia, diarrhea, and pneumonia. Therefore, in the course of immunotherapy, doctors need to fully understand potential adverse reactions and closely monitor patients. If adverse reactions occur, treatment should be implemented as soon as possible, and preventing patients from organ dysfunction and death is the key to successful treatment.

The management of irAEs depends on their severity, which is assessed using the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0) (41). Grade 1 (mild) events generally allow continuation of immunotherapy with close observation. In contrast, grade 2 (moderate) events often require temporary suspension of immune checkpoint inhibitors and the initiation of corticosteroids, such as prednisone at a dose of 0.5–1 mg/kg/day. For grade 3 or higher (severe) toxicities, permanent discontinuation of immunotherapy is typically necessary, along with the administration of high-dose corticosteroids (1–2 mg/kg/day). In steroid-refractory cases—particularly with colitis or pneumonitis—additional immunosuppressive agents such as infliximab may be indicated. Prompt identification and early intervention are essential to reducing morbidity, preventing irreversible organ damage, and maintaining the overall continuity of cancer immunotherapy.

Discussion and outlook

Over the past decade, PD-1/PD-L1 immune checkpoint inhibitors have transitioned from experimental second-line treatments to well-established first-line therapies for NSCLC. Numerous large-scale clinical trials—such as KEYNOTE-189, KEYNOTE-407, and IMpower110—have validated their efficacy in prolonging survival across diverse patient populations, and these agents are now central to frontline treatment strategies (31-33,37). Mechanistically, PD-1/PD-L1 inhibitors restore anti-tumor T cell activity by relieving inhibitory signaling in the TME, thereby reversing immune suppression and reinvigorating effector responses (42,43).

Despite their success, immune checkpoint inhibitors are not universally effective. A substantial proportion of patients fail to respond initially (primary resistance) or relapse after an initial benefit (acquired resistance). These failures are driven by complex mechanisms, including loss of antigen presentation, alterations in oncogenic pathways, expansion of immunosuppressive cells (e.g., Tregs, MDSCs), and T cell exhaustion (44,45). Consequently, a critical challenge in the field is to overcome such resistance and improve long-term outcomes.

To that end, several next-generation immunotherapeutic strategies are being explored. Bispecific antibodies targeting both PD-L1 and other suppressive mediators, such as TGF-β, offer the ability to modulate multiple resistance pathways simultaneously. Furthermore, emerging immune checkpoints such as TIGIT and LAG-3 have gained traction as targets for combinatorial regimens. For example, tiragolumab, a TIGIT inhibitor, has shown promising results when combined with atezolizumab in PD-L1-positive NSCLC patients in the CITYSCAPE trial and ongoing SKYSCRAPER-01 study (46). Similarly, relatlimab, a LAG-3-blocking antibody, demonstrated improved PFS when combined with nivolumab in the RELATIVITY-047 study in melanoma, and is under investigation in lung cancer (47). A mechanistic study further supports LAG-3’s role in promoting T cell dysfunction, making it a compelling co-target with PD-1 blockade (48).

Looking ahead, the continued evolution of lung cancer immunotherapy will depend on integrating immune phenotyping, biomarker-driven patient selection, and rational combination therapy. As our understanding of the tumor-immune interface deepens, the development of tailored immunotherapeutic approaches holds promise to overcome resistance and extend durable responses to a broader range of patients.

Conclusions

In conclusion, while PD-1/PD-L1 inhibitors have revolutionized the treatment of NSCLC, several clinical and biological challenges remain. These include resistance, toxicity, and limited biomarker guidance, which restrict the scope of durable benefit. Future efforts should focus on rational combination therapies, immune phenotype–based patient selection, and integrated biomarker strategies to optimize treatment outcomes. Table 2 provides an overview of these challenges, their mechanistic basis, and potential research directions to guide the next phase of immunotherapy development.

Table 2. Immunotherapy challenges and strategies.

Current challenges	Underlying mechanisms	Future strategies
Primary and acquired resistance	Loss of antigen presentation; T cell exhaustion	Dual checkpoint blockade (e.g., PD-1 + TIGIT/LAG-3)
Limited predictive biomarkers	PD-L1 expression alone is insufficient; TMB variability	Use of composite biomarkers (PD-L1 + TMB + TILs)
Immune-related adverse events (irAEs)	Systemic immune activation; autoimmunity	Biomarker-guided toxicity prediction; steroid-sparing agents
Incomplete tumor immune infiltration	Stromal barriers; VEGF-mediated exclusion	Anti-VEGF combination; TME remodeling
Lack of personalized immunotherapy	Heterogeneity in immune microenvironment	Immune phenotype-based therapy selection

PD-1, programmed death receptor 1; PD-L1, programmed death ligand 1; TILs, tumor-infiltrating lymphocytes; TMB, tumor mutation burden; TME, tumor microenvironment; VEGF, vascular endothelial growth factor.

Supplementary

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