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Next-Generation Immunotherapy Strategies Driven by Tumor Microenvironment Modulation

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Next-Generation Immunotherapy Strategies Driven by Tumor Microenvironment Modulation

Xianfeng Hui 1,2,3,* Ge Gao 4 Shihuan Ding 1,3 Shuoxiang Gao 1 Jiaqi Tian 5 Shuochen Xu 1,2,3 Tiesuo Zhao 1,3 Hui Wang 1,2

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1
Department of Immunology, School of Basic Medical Sciences, Henan Medical University, Xinxiang 453003, China
2
Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Henan Medical University, Xinxiang 453003, China
3
Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Henan Medical University, Xinxiang 453003, China
4
School of Nursing, Henan Medical University, Xinxiang 453003, China
5
College of Medicine, Henan University, Kaifeng 475001, China
*
Authors to whom correspondence should be addressed.

Received: 13 February 2026 Revised: 28 April 2026 Accepted: 25 May 2026 Published: 01 June 2026

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© 2026 The authors. This is an open access article under the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

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Immune Discov. 2026, 2(2), 10003; DOI: 10.70322/immune.2026.10003
ABSTRACT: Next-generation cancer immunotherapy increasingly recognizes the tumor microenvironment (TME) as a decisive regulator of therapeutic efficacy and durability. While immune checkpoint blockade and other immunotherapies have achieved remarkable clinical success, sustained benefit remains limited to a subset of patients, underscoring the insufficiency of immune activation alone. Accumulating evidence reveals that the TME functions as a dynamic immune ecosystem that shapes immune cell infiltration, metabolic fitness, spatial organization, and effector function. Static or reductionist biomarker frameworks fail to capture the temporal and functional heterogeneity of TME states that govern immunotherapy sensitivity and resistance. Importantly, immunotherapeutic interventions themselves induce adaptive TME remodelling, frequently triggering compensatory immunosuppressive circuits and acquired resistance. In this review, we synthesize recent advances in understanding functional and evolving TME states and discuss how strategic modulation of the microenvironment can enable more durable and context-dependent immunotherapy responses. By reframing immunotherapy as a process of TME state management rather than isolated immune stimulation, this perspective outlines guiding principles for designing adaptive, TME-driven immunotherapeutic strategies.
Keywords: Tumor microenvironment; Immunotherapy resistance; TME; Adaptive immunotherapy
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