Jul 2026· Health Dynamics· 0 citations· 54 references
TL;DR
It is found that ICI monotherapy significantly improves overall survival in NSCLC with PD-L1 expression ≥50% compared with platinum-based chemotherapy, and first-line atezolizumab plus chemotherapy extended median overall survival to 12.3 months, compared with 10.3 months in extensive-stage SCLC.
Abstract
Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases and small cell lung cancer (SCLC) representing a highly aggressive neuroendocrine subtype with a poor prognosis. Tumor cells evade immune surveillance by co-opting immune checkpoint pathways, principally programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). This review evaluates the mechanisms and therapeutic potential of PD-1 and CTLA-4 blockade in overcoming immune evasion in lung cancer. A structured narrative literature review synthesized evidence from preclinical studies, landmark clinical trials including KEYNOTE-001 and IMpower133, biomarker investigations, and mechanistic research on PD-1/PD-L1 and CTLA-4 pathways in NSCLC and SCLC. PD-1 suppresses effector T-cell activity and enhances regulatory T-cell function within the tumor microenvironment, while CTLA-4 attenuates T-cell priming through competitive B7 ligand binding. Immune escape is further mediated by HLA class I downregulation, impaired antigen presentation, immunosuppressive cytokine signaling, and tumor-infiltrating regulatory T cells. ICI monotherapy significantly improves overall survival in NSCLC with PD-L1 expression ≥50% compared with platinum-based chemotherapy. First-line atezolizumab plus chemotherapy extended median overall survival to 12.3 months, compared with 10.3 months in extensive-stage SCLC. Dual PD-1/CTLA-4 blockade produces synergistic antitumor responses; however, 70–85% of NSCLC patients develop primary or acquired resistance. PD-1 and CTLA-4 blockade has transformed the therapeutic landscape of lung cancer, yet resistance mechanisms, immune-related adverse events, and the absence of validated predictive biomarkers remain critical challenges. Future research must prioritize combination strategies, novel checkpoint targets, and multifactorial biomarker panels to broaden clinical benefit.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally, with limited effective treatments and a generally poor prognosis. Immune checkpoint pathways, particularly PD-1/PD-L1 and CTLA-4, play a crucial role in modulating the tumor microenvironment (TME) and facilitating immune escape in HCC. PD-1 is expressed on activated T cells, B cells, and macrophages, and interacts with PD-L1, which is often overexpressed on tumor cells and antigen-presenting cells. This interaction leads to T-cell inhibition and tumor immune evasion. Elevated PD-1/PD-L1 expression in HCC correlates with disease progression and poor outcomes. Inhibitors targeting PD-1 or PD-L1 have shown significant clinical benefits in some HCC patients, highlighting the therapeutic potential of this pathway. CTLA-4, another critical checkpoint molecule, negatively regulates immune responses by competing with CD28 for B7 binding on antigen-presenting cells, thereby dampening T-cell activation and proliferation. In HCC, CTLA-4 expression contributes to immune suppression and tumor growth. CTLA-4 blockade combined with PD-1/PD-L1 inhibitors has shown promise in enhancing anti-tumor immunity and improving clinical outcomes in HCC patients. The complex interplay between PD-1/PD-L1 and CTLA-4 pathways in HCC underscores the complexity of immune escape mechanisms. Targeting these checkpoints has the potential to reshape HCC treatment, offering hope for more effective and durable outcomes. Future research should focus on optimizing combination therapies, understanding resistance mechanisms, and identifying biomarkers for better patient stratification and response prediction. Advancements in this field could lead to more personalized and effective treatments, significantly improving the prognosis and quality of life for HCC patients.
K. Sharma, Hema Barti, Siddhant Jai Tyagi et al.· Current Gene Therapy· 0 citations
Immune checkpoint inhibition has transformed the treatment of advanced non-small cell lung cancer (NSCLC), but primary and acquired resistance remain common. Vascular endothelial growth factor (VEGF) contributes to both tumor angiogenesis and immune suppression by promoting abnormal vasculature, limiting lymphocyte trafficking, and fostering an immunosuppressive tumor microenvironment. These complementary mechanisms provide a rationale for simultaneously targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and VEGF pathways. Bispecific antibodies integrating checkpoint blockade and VEGF neutralization within a single molecule have therefore emerged as a rapidly developing therapeutic strategy in NSCLC. Ivonescimab, a PD-1/VEGF bispecific antibody, currently has the most mature evidence, with randomized phase III trials demonstrating improvements in progression-free survival and, in selected settings, overall survival compared with established PD-1-based regimens. Other PD-1/VEGF agents, including PF-08634404, MK-2010, and JS207, have shown encouraging early activity but require randomized validation. Among PD-L1/VEGF bispecific antibodies, pumitamig, HB0025, and IMM2510 have demonstrated promising antitumor activity, although evidence is derived predominantly from early-phase or single-arm studies. Multiple phase III trials are evaluating these agents in first-line, post-immunotherapy, epidermal growth factor receptor (EGFR)-mutated, and stage III consolidation settings. VEGF-associated toxicities, including hypertension, proteinuria, hemorrhage, and thromboembolism, remain clinically relevant. Moreover, differences in checkpoint target, molecular architecture, target affinity, fragment crystallizable (Fc) engineering, pharmacokinetics, and VEGF-binding strategy preclude the assumption of a uniform class effect. The fixed bispecific configuration also prevents independent dose adjustment of the checkpoint and antiangiogenic components, which may complicate toxicity management. Mature randomized survival data, longer-term safety assessment, and biomarker development are needed to define optimal patient selection and the clinical role of PD-(L)1/VEGF bispecific antibodies in NSCLC.
Aleena Kuriakose, Salem Gogah, E. Beleva· Journal of Clinical Question...· 0 citations
Non-small-cell lung cancer (NSCLC) is a major contributor to cancer-related deaths worldwide. Although the introduction of immune checkpoint inhibitors, such as anti-PD-1, has improved patient survival, treatment responses remain heterogeneous, and the complete mechanisms of action are not yet fully understood. Our group previously described naturally immune checkpoint blockade mediated by endogenous antibodies that functionally mimic the effects of therapeutic checkpoint inhibitors, without autoimmune symptoms in non-previously treated NSCLC patients (Frozza et al., 2025, under review). Now we are investigating the immune profile of NSCLC patients undergoing neoadjuvant anti-PD-1 therapy combined with chemotherapy, with the hypothesis that the presence and dynamic modulation of circulating anti-PD-L1 autoantibodies influence the tumor immune microenvironment, thereby impacting treatment response, immune activation, and therapeutic efficacy.
To achieve this, transcriptomic profiling through single-cell RNA sequencing (scRNAseq) of immune cells from blood, tumor and draining lymph node are being performed pre and post treatment, following by the validation with flow cytometry and immunohistochemistry. The quantification of autoantibodies anti-PD-L1 are being performed by ELISA.
Preliminary analyses demonstrate the presence of circulating anti—PD-L1 autoantibodies both before and after chemo-immunotherapy. Post-treatment antibody levels exhibited marked variability, suggesting heterogeneous immune modulation in response to treatment. scRNAseq showed an increase in the frequency of the CD8+ T and B cell infiltrating the tumor and draining lymph nodes post treatment.
In conclusion, this study seeks to elucidate mechanisms of immunotherapy resistance in NSCLC by linking tumor immune profiles and the presence of anti—PD-L1 autoantibodies to responses to neoadjuvant chemo-immunotherapy, with the goal of identifying predictive biomarkers and improving treatment strategies.
PRONON (25000.172780/2019-38), RITEs/FAPERGS (22/2551-0000388-5), FINEP (3088 and 3098), and Universal (405768/2024-0).
Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
V. Pscheidt, F. Frozza, S. Soder et al.· Journal of Immunology· 0 citations
Background CTLA-4/CD80 and PD-1/PD-L1 immune checkpoint pathways play critical roles in regulating T-cell activity within the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC). While immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have improved survival outcomes, response rates vary, and predictive biomarkers’ alternative to PD-L1 expression are imperative. Our study aimed to identify PD-1/PD-L1 and CTLA-4/CD80 interaction states as enhanced predictive biomarkers for patient stratification to anti-PD-1/PD-L1 therapies in NSCLC. Methods This study utilized the QF-Pro® platform to quantify CTLA-4/CD80 and PD-1/PD-L1 interaction states in formalin-fixed paraffin-embedded (FFPE) samples from a cohort of 67 NSCLC patients treated with anti-PD-1/PD-L1 therapies. Corroborating prior findings, high PD-1/PD-L1 interaction, measured by FRET efficiency, predicts improved response rates via overall survival (OS) and progression-free survival (PFS). Results Remarkably, we also identified high CTLA-4/CD80 interaction (FRET efficiency ≥6.41%) as correlating with improved OS and PFS in response to anti-PD-1/PD-L1 therapies. Patients with concurrently high PD-1/PD-L1 and CTLA-4/CD80 interactions exhibited the highest response rates, suggesting synergistic interplay between these checkpoints. In contrast, neither biomarker predicted response to chemotherapy in a separate cohort of 51 lung adenocarcinoma patients, confirming specificity for ICI therapy. Conclusions These results highlight the potential of QF-Pro® as a robust tool for stratifying NSCLC patients for ICI treatment and underscore the clinical relevance of CTLA-4/CD80 interaction as a predictive biomarker, paving the way for personalized immunotherapy strategies.
J. Gumuzio, J. Miles, Nicole Quimi et al.· Frontiers in Immunology· 1 citation
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a key immune checkpoint in Gastrointestinal system cancers (GSCs), inhibiting T-cell activation by outcompeting CD28 for B7-1/B7-2 binding on antigen-presenting cells, thereby promoting immune evasion. Its overexpression correlates with advanced stage, poor survival, and worse prognosis in gastric, colorectal, esophageal, and pancreatic cancers. CTLA-4 blockade with Ipilimumab or Tremelimumab shows promise, especially combined with PD-1/PD-L1 inhibitors, yielding enhanced antitumor immunity in microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) tumors with high immune infiltration. However, efficacy is limited by tumor heterogeneity and an immunosuppressive microenvironment enriched in CTLA-4⁺ regulatory T cells (Tregs). Inconsistent clinical responses underscore the need for predictive biomarkers, optimized combinations, and mechanistic insights into resistance. This review explores CTLA-4's role in GSCs, highlighting microenvironment-focused strategies to improve precision and therapeutic outcomes.
Fuyuan Ma, Jingyuan Ma, Yaofan Lu et al.· American Journal of the Medi...· 0 citations
Abstract Immune checkpoint inhibition has revolutionized the management of microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR) metastatic colorectal cancer (mCRC), a biologically distinct subgroup characterized by high tumor mutational burden, neoantigen richness, and marked immune infiltration. Programmed death-1 (PD-1) inhibitors, such as pembrolizumab and nivolumab, have demonstrated durable responses and improved outcomes compared with historical chemotherapy, including in the first-line setting. Nevertheless, a clinically relevant proportion of patients exhibit primary resistance or early progression on PD-1 monotherapy. This unmet need has driven interest in dual immune checkpoint blockade combining PD-1 and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) inhibition. Mechanistically, CTLA-4 blockade enhances T-cell priming and repertoire diversification, complementing PD-1–mediated reinvigoration of tumor-infiltrating effector T cells. Clinical studies indicate that nivolumab plus ipilimumab is associated with higher objective response rates and longer progression-free survival compared to PD-1 monotherapy. Recent randomized data from the Checkmate 8HW trial suggest a clinically meaningful trend toward improved overall survival with combination therapy; however, overall survival data are not yet mature and definitive conclusions regarding survival benefit cannot be drawn.
L. Esposito, B. Ceredi, C. Gallio et al.· ONCOLOGIE· 0 citations