Next-Generation Immunotherapy Strategies Driven by Tumor Microenvironment Modulation

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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