Immune Checkpoint: A Critical Target In Tumor Therapy

Immune checkpoints are inhibitory or costimulatory pathways that regulate T-cell activation, peripheral tolerance, and antitumor immune responses, and tumors can exploit these pathways to restrict effector T-cell function and establish immune escape. CTLA-4 mainly acts during T-cell priming by competing with CD28 for CD80/CD86 costimulation, whereas PD-1 suppresses TCR downstream signaling, cytokine production, and cytotoxic activity through binding PD-L1 or PD-L2, making CTLA-4, PD-1, and PD-L1 the most clinically validated targets in tumor immunotherapy. Clinical studies showed that the anti-CTLA-4 antibody ipilimumab improved survival in metastatic melanoma, that anti-PD-1 antibody produced objective responses in melanoma, non-small-cell lung cancer, and renal-cell cancer, and that anti-PD-L1 antibody also showed antitumor activity in patients with advanced cancer^{[1][2][3][4][5]}.
Immune checkpoint blockade has become a major drug-discovery direction for melanoma, lung cancer, renal cancer, colorectal cancer, and other solid tumors, and experimental design commonly evaluates T-cell infiltration, PD-L1 expression, antigen presentation, tumor mutational burden, mismatch-repair deficiency, and immunosuppressive tumor microenvironment features. Nivolumab plus ipilimumab improved efficacy in untreated melanoma, and PD-1 blockade showed activity across mismatch-repair-deficient tumors, supporting the use of immune checkpoint targeting with molecular classification and immune phenotyping for patient stratification. Current barriers include primary resistance, adaptive resistance, acquired resistance, immune-related adverse events, insufficient response prediction, and increased toxicity from combination regimens; future research should prioritize mechanism-defined resistance models, validated biomarkers, lower-toxicity combinations, and translational systems that capture dynamic tumor-immune interactions^{[6][7][8][9][10]}.