Combination Immunotherapy as a Promising Strategy to Overcome Immunotherapy Resistance: From Emergence to Next-Generation Approaches.

Advances in immunotherapy, particularly with immune checkpoint inhibitors, have improved clinical outcomes in various cancer subtypes; however, resistance often occurs because these treatments rely on single agents and show limited translational success when combined. Therefore, it is necessary to develop immune checkpoint inhibitor-based combination strategies by integrating next-generation immunotherapies and innovative biomarkers. This review highlights the emerging combinatorial approaches that can be tailored to the distinct tumor microenvironment types to overcome resistance to immune checkpoint inhibitors. It further emphasizes the rationale for integrating advanced biomarkers to predict response and personalize immunotherapy, highlighting the importance of combining next-generation immunotherapies with immune checkpoint inhibitors and including them in current clinical trial designs. Building on this foundation, we integrate key lessons from failed clinical trials and the spectrum of toxicities associated with combination immunotherapy. Finally, we outline approaches for early biomarker discovery and clinical translation, including the incorporation of validated artificial intelligence-driven biomarker platforms into adaptive, biomarker-guided trial designs.