Transforming cancer immunotherapy: integration of distinct immune-based approaches as redefined dual immunotherapy with potential third-sensitizer.

This review introduces a paradigm-shifting concept of Dual Distinct Immunotherapy (DDI), which strategically integrates two distinct immunotherapeutic modalities to overcome the limitations of current monotherapies and dual immune checkpoint inhibitor (ICI) combinations. The concept of DDI extends beyond traditional ICI combinations to encompass various innovative pairings: ICIs with oncolytic viruses (OVs), adoptive cell therapies (CAR-T/TIL), cancer vaccines, or cytokine therapies. These combinations demonstrate unique synergistic mechanisms and enhanced therapeutic potential through multi-faceted immune activation. Significantly, this work advances the field by analyzing potential third-agent sensitizers to complement DDI strategies. We systematically evaluate emerging candidates including PCNA inhibitors, HDAC inhibitors, and carbonic anhydrase inhibitors, focusing on their ability to modulate the tumor microenvironment and enhance immunotherapy responses. This "DDI + 1" approach targets alternative pathways to overcome resistance mechanisms and expand treatment efficacy to traditionally immunotherapy-resistant cancers. Through comprehensive analysis of preclinical evidence and ongoing clinical trials, we address critical challenges in immunotherapy, including primary and acquired resistance, cold tumor conversion, and pathway exhaustion. The review synthesizes current findings while proposing innovative solutions and future research directions. Our framework demonstrates how strategic integration of multiple immune-based approaches can significantly improve therapeutic outcomes across diverse cancer types, potentially revolutionizing cancer treatment paradigms. This concept of DDI, enhanced by rational third-agent selection, represents a promising direction for addressing urgent clinical needs in oncology. By establishing a theoretical foundation for this approach, we aim to guide future research and clinical applications in cancer immunotherapy.