The mechano-immunological landscape in the tumor microenvironment: From mechanical sensing to a new therapeutic paradigm.

The tumor microenvironment (TME) is a complex ecosystem where mechanical forces are now recognized not as passive byproducts but as active drivers critically shaping anti-tumor immunity. This review introduces the integrative concept of the "Mechano-immunological Landscape" (MIL) to delineate the dynamic and spatially heterogeneous network of interactions between mechanical cues and immune cells within tumors. We systematically elaborate on its three core pillars: Mechano-immunological Checkpoints, Mechano-immune Memory, and Landscape Plasticity. Building upon this framework, we propose a novel therapeutic paradigm termed "Mechano-immunological Landscape Remodeling Therapy" (MILRT). This paradigm discusses potential strategies to reverse immune suppression and enhance anti-tumor efficacy by modulating the mechanical TME, including matrix de-stiffening, mechanical empowerment of immune cells, and targeting mechano-immunological checkpoints. Finally, we outline future research trajectories, pivotal challenges, and clinical translation prospects in this burgeoning field. We position MILRT as a multi-pronged and synergistic framework that leverages advanced biomaterials and biophysical tools to overcome current limitations in drug delivery and immunotherapy resistance, thereby paving the way for next-generation, mechano-aware immunotherapies and redefining the future of solid tumor treatment.