Dual immune checkpoint blockade strategies for cancer therapy

The application of immune checkpoint inhibitors (ICIs) has transformed the treatment paradigm for advanced malignancies and has significantly improved the clinical outcomes of patients with various solid tumors. However, the overall response rate to ICI monotherapy remains limited, and some patients may develop resistance. By targeting multiple immune checkpoints (ICs), combination therapeutic strategies can achieve significant synergistic effects, which can more comprehensively relieve the suppression of the immune system by tumors, thereby increasing therapeutic efficacy. This review summarizes studies on ICI combination therapy; elucidates the mechanisms of action of IC molecules; analyzes the theoretical rationale, preclinical studies, and clinical outcomes of dual ICI combinations; and discusses the safety profiles, tolerability, and management strategies for adverse effects associated with combination therapies. Furthermore, the predictive biomarkers for the efficacy of ICI combination therapy, including programmed death-ligand 1 (PD-L1) expression and the tumor mutational burden (TMB), as well as emerging biomarkers such as the gut microbiota and circulating tumor DNA (ctDNA), are summarized. The importance of the coexpression of IC molecules in predicting the prognosis of cancer patients is emphasized. Future research directions are also proposed, including the exploration of precise biomarkers and the optimization of dosing regimens. Although combination ICI therapy holds great potential, further research is necessary to increase its efficacy and safety, ultimately achieving precision cancer immunotherapy.