Adaptive resistance in cancer immunotherapy

Abstract Despite revolutionizing oncology, cancer immunotherapy benefits only a minority of patients partly because of adaptive resistance. This resistance tends to manifest in two distinct clinical scenarios. The first is characterized by disease progression during treatment following an initial response, driven primarily by insufficient tumor-killing capacity. The second is characterized by relapse after initial remission, resulting from a failure to establish durable antitumor immune memory (AIM). Underlying both patterns is the progressive functional exhaustion of tumor-specific T cells, which reflects a dynamic equilibrium between immune attack and tumor evasion, a balance that is continuously challenged within an immunosuppressive tumor microenvironment (TME) sculpted by immunoediting. This review provides a comprehensive synthesis of current knowledge on adaptive resistance to cancer immunotherapy, with a particular emphasis on the mechanistic contributions of dysfunctional T-cell responses. We begin by outlining the frameworks of cancer immunoediting and AIM, detailing how exhausted T cells undermine sustained immunotherapeutic efficacy, and summarizing the achievements and limitations of current regimens. We then delineate how T-cell dysfunction, particularly within the TME and tumor-draining lymph nodes, culminates in adaptive resistance to immunotherapy, manifesting as either insufficient tumor-killing capacity leading to on-treatment progression or failure to establish durable AIM resulting in postremission relapse. A systematic analysis of the cellular and molecular drivers of this exhausted state follows, integrating established paradigms and highlighting key knowledge gaps. Finally, we critically evaluate emerging rejuvenation strategies, translational approaches for next-generation therapies, persistent challenges and promising directions for future research.