Research progress on the molecular mechanisms of PD-1 and LAG-3 synergy in regulating T cell exhaustion and immunotherapy

BACKGROUND: PD-1 and LAG-3 are immune checkpoint molecules frequently co-expressed in the tumor microenvironment, where they synergistically drive T-cell exhaustion and immune escape. Dual blockade of these pathways represents a promising strategy to overcome immunotherapy resistance. METHODS: This review systematically synthesizes mechanistic studies on PD-1/LAG-3 synergy and summarizes preclinical and clinical advances in dual blockade therapies, with emphasis on bispecific antibodies and combination trial data. RESULTS: complementary signaling pathways. Combined inhibition substantially restores antitumor immunity. A PD-1/LAG-3 bispecific antibody has been approved for melanoma, with numerous trials ongoing across other malignancies. CONCLUSION: Despite demonstrated efficacy, challenges including variable response rates, resistance mechanisms, and immune-related adverse events remain. Future efforts should prioritize biomarker identification and regimen optimization to enable precision application of dual blockade.