Volume 127

Immune checkpoint inhibitors (ICIs), which target novel immune receptors including programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), lymphocyte activation gene-3 (LAG-3), T-cell immunoglobulin and ITIM domain (TIGIT), and T-cell immunoglobulin and mucin domain 3 (TIM-3), have profoundly reshaped cancer treatment paradigms. Tumors exploit these signaling pathways to suppress T-cell activation and impair immune surveillance. By interrupting inhibitory signaling, ICIs mechanistically restore antitumor immune responses. In clinical practice, ICIs have demonstrated durable efficacy and wide-ranging applicability across multiple solid tumors, markedly increasing overall survival (OS) when utilized as monotherapy or in combination with chemotherapy or anti-angiogenic therapies. Nonetheless, significant clinical challenges persist, including heterogeneous patient responses, only approximately 20–40% achieve sustained remission, and immune-related adverse events (irAEs) affecting around 50–70% of recipients. Additionally, existing biomarkers, such as programmed cell death-ligand 1 (PD-L1) expression levels and tumor mutation burden, exhibit limited predictive accuracy across different cancer types. Moreover, irAEs, including severe pneumonitis and endocrine toxicities, require specialized clinical management. Moving forward, research should emphasize developing multi-omics-based biomarkers, refining combination treatment regimens, and unraveling resistance mechanisms to improve the precision and effectiveness of immunotherapy.

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