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

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.