Factors influencing the efficacy of programmed cell death protein 1 / programmed death-ligand 1 inhibitors in non-small cell lung cancer

Efficacy and safety of Programmed Death Ligand 1 inhibitors versus Programmed Death 1 inhibitors in the first-line treatment of advanced non-small cell lung cancer: a meta-analysis of randomized controlled trials

Background With the increasing use of immune checkpoint inhibitors (ICIs) in the first-line treatment of driver mutation-negative non-small cell lung cancer (NSCLC), we conducted a systematic review and meta-analysis to compare efficacy and adverse effects (AEs) between PD-L1 inhibitors and PD-1 inhibitors. Methods We searched PubMed, Web of Science, Embase, and the Cochrane Library to identify randomized controlled trials (RCTs) related to the first-line treatment of NSCLC with ICIs alone or in combination with chemotherapy. The primary outcomes were overall survival (OS), progression-free survival (PFS), and AEs. Results In total, 28 RCTs involving 14,758 patients were included. Compared with Programmed Death 1 (PD-1) inhibitors plus chemotherapy, Programmed Death Ligand 1 (PD-L1) inhibitors plus chemotherapy were associated with worse OS (hazard ratio (HR) = 1.26; 95% confidence interval (CI) [1.13–1.41]; P < 0.001) and PFS (HR = 1.21; 95% CI [1.06–1.38]; P = 0.005). The objective response rate (ORR) did not differ between PD-1 inhibitors plus chemotherapy and PD-L1 inhibitors plus chemotherapy (odds ratio (OR) = 0.91; 95% CI [0.78–1.05], P = 0.205), and AE rates were similar between these groups. Regarding monotherapy, no difference in OS, PFS, or ORR was observed between PD-L1 and PD-1 inhibitors. The incidence of AEs leading to treatment termination and grade ≥3 AEs was lower for PD-L1 inhibitors than PD-1 inhibitors (risk ratio (RR) = 0.55; 95% CI [0.32–0.95]; P = 0.03; RR = 0.76; 95% CI [0.60–0.96]; P = 0.021). Conclusions The combination of PD-1 inhibitors and chemotherapy may provide a significant OS and PFS benefit relative to PD-L1 inhibitors plus chemotherapy in NSCLC and a similar safety profile. Meanwhile, PD-L1 inhibitor monotherapy appears less likely to result in treatment termination or grade ≥3 AEs than PD-1 inhibitor monotherapy.

Primary and acquired resistance to immunotherapy in NSCLC

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer incidence and mortality worldwide. In recent years, immune checkpoint inhibitors (ICIs), particularly those targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) axis, have significantly improved survival outcomes in a subset of patients. However, the magnitude and durability of clinical benefit vary considerably according to PD-L1 expression, treatment setting, histological subtype, oncogenic driver status, and whether ICIs are administered as monotherapy or in combination regimens. A substantial proportion of patients therefore exhibit either primary resistance or acquired resistance after an initial response. This review systematically summarizes the key mechanisms underlying immune resistance in lung cancer. These include defects in antigen presentation, such as abnormalities in major histocompatibility complex class I (MHC-I), transporter associated with antigen processing 2 (TAP2), and β2-microglobulin (B2M), as well as dysregulation of the interferon-γ/Janus kinase-signal transducer and activator of transcription (IFN-γ/JAK-STAT) signaling pathway. Tumors frequently exhibit an immune-excluded or ‘cold’ phenotype, which further limits immune recognition and reduces responsiveness to immunotherapy. This review summarizes immune resistance in NSCLC through a framework that distinguishes primary resistance from acquired resistance. Primary resistance reflects failure of immune activation at treatment initiation, usually due to pre-existing tumor-intrinsic or microenvironmental barriers, including impaired antigen presentation, defective IFN-γ/JAK-STAT signaling, low tumor immunogenicity, immune-cold or immune-excluded phenotypes, and suppressive TME states. In contrast, acquired resistance reflects adaptive tumor and immune ecosystem evolution under therapeutic pressure, leading to neoantigen loss, HLA or B2M alterations, compensatory checkpoint activation, progressive T cell exhaustion, TME remodeling, and epigenetic stabilization of immune escape. We further discuss mechanism-based biomarkers, translational correlates, and rational therapeutic strategies for overcoming resistance.

Expanding indications of immune checkpoint inhibitors: a decade of success going strong.

INTRODUCTION Immune checkpoint inhibitors (ICIs) have transformed oncology by targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1), thereby enabling responses across multiple malignancies. Despite these advances, benefits remain limited in many cancers. AREAS COVERED A narrative literature review was conducted using PubMed, Embase, and the Cochrane Library to identify English-language publications from 1 January 2000, through 31 December 2025. Eligible sources included pivotal trials, real-world studies, reviews, and relevant clinical practice guidelines. EXPERT OPINION Since 2011, ICIs have permeated virtually all fields of oncology, with meaningful impact across many cancer types. Beyond expanding indications, they offer potential for durable benefit in many responders. In melanoma, head and neck, kidney, liver, and urothelial cancers, PD-L1 testing outside clinical trials is no longer required. Tumor-agnostic efficacy of PD-1 ± CTLA-4 inhibition in microsatellite instability-high cancers is well established. Limited benefit in other cancer subsets highlights the need for biomarker discovery and optimization of therapeutic strategies, including addition of antibody-drug conjugates to ICIs, next-generation checkpoint modulation, personalized neoantigen vaccines, and engineered cellular immunotherapy. Effective future therapies should also address comprehensive profiling of tumor cells, their molecular expression patterns, and constantly changing dynamics of the tumor microenvironment.

Next-Generation Checkpoint Combinations: Optimizing PD-(L)1–Based Therapy Across the Advanced, Adjuvant, and Neoadjuvant Settings

The Role of PD-1 and CTLA-4 Blockade in Immunotherapy: Mechanisms of Action and Therapeutic Efficacy in Overcoming Lung Cancer Immune Evasion

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.

Mechanisms underlying the failure of PD-1/PD-L1 blockade in glioblastoma: Therapeutic challenges and opportunities

Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis and limited therapeutic options. Although programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade has transformed the treatment of several malignancies, its clinical benefit in GBM remains limited, and the mechanisms underlying this resistance remain poorly understood.​ This review summarizes the biological roles of the PD-1/PD-L1 axis in the GBM microenvironment, evaluates clinical evidence for immune checkpoint inhibitors, and discusses mechanisms of resistance and strategies to overcome therapeutic resistance.​ It integrates current preclinical and clinical evidence on PD-1/PD-L1 signaling, the cellular sources of PD-L1, clinical trial outcomes, resistance mechanisms, and emerging combination strategies.​ We propose a dual-source PD-L1 framework to discuss the potential contributions of tumor cell-derived and immune cell-derived PD-L1 to GBM-mediated immunosuppression and therapeutic response. However, whether these two PD-L1 sources have distinct functional specializations remains unproven and requires further validation through spatial omics analyses and cell-type-specific functional studies. This framework may help explain the limited value of total PD-L1 expression as a single predictive biomarker in GBM. We further outline a multilayer resistance model involving the blood–brain barrier, an immunologically cold tumor microenvironment, and compensatory immunosuppressive networks. Emerging strategies, including optimized treatment timing, microenvironmental modulation, and rational immunotherapy combinations, are also discussed.​ A deeper understanding of PD-1/PD-L1 biology and multilayered immune resistance may guide the development of more effective immunotherapeutic strategies for GBM.