Adaptive resistance in cancer immunotherapy
5 affiliations
- 1Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. [email protected]
- 2Institute of Immunological Innovation and Translation, Chongqing Medical University, Chongqing, China. [email protected]
- 3Institute of Immunological Innovation and Translation, Chongqing Medical University, Chongqing, China
- 4Changping Laboratory, Beijing, China. [email protected]
- 5Institute of Immunology, Third Military Medical University, Chongqing, China. [email protected]
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.
Related
- Overcoming adaptive resistance in non-small cell lung cancer: integrating targeted therapies, immunotherapy synergy, and nanocarrier delivery
- 944 Succinate-based metabolic reprogramming of innate and adaptive immunity for ovarian cancer immunotherapy
- Targeting the Tumor Microenvironment Network to Overcome Immunotherapy Resistance in Non‐Small Cell Lung Cancer: Mechanisms to Clinical Translation
- MSRB3 promotes gastric cancer progression and immunotherapy resistance by stabilizing GPX4 to inhibit ferroptosis
- Molecular mechanisms and therapeutic strategies of immunotherapy resistance in esophageal cancer
BibTeX
@article{yang2026adaptive,
title = {{Adaptive resistance in cancer immunotherapy}},
author = {K E Yang and Chunqian Yang and Kai Xiong and Jiangtao Hao and Lilin Ye},
journal = {Cellular and Molecular Immunology},
year = {2026},
month = may,
doi = {10.1038/s41423-026-01424-9},
url = {https://doi.org/10.1038/s41423-026-01424-9},
note = {CC BY},
}
RIS
TY - JOUR
TI - Adaptive resistance in cancer immunotherapy
AU - K E Yang
AU - Chunqian Yang
AU - Kai Xiong
AU - Jiangtao Hao
AU - Lilin Ye
PY - 2026
DA - 2026/05/20
JO - Cellular and Molecular Immunology
DO - 10.1038/s41423-026-01424-9
UR - https://doi.org/10.1038/s41423-026-01424-9
AB - 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.
SN - 1672-7681
SN - 2042-0226
ER -