Hydrogel-based reprogramming of the tumor inflammatory microenvironment: from mechanotransduction and dynamic...

Modulating inflammation within the tumor microenvironment (TME) has emerged as a crucial avenue in contemporary cancer therapy. However, the intricate signaling networks, mechanical heterogeneity, spatiotemporal drug gradients, and poor immune cell infiltration continue to hinder the effectiveness of conventional therapeutic strategies. Hydrogels, with tunable physicochemical properties and versatile biological functions, offer a promising platform for addressing these challenges. This review first unpacks the inflammatory pathways active in the TME and then provides a structured overview of hydrogel classifications and material characteristics. From there, it discusses how mechanotransduction pathways (e.g., YAP/TAZ, Piezo1, FAK) and chemical signaling frameworks shape the interaction between hydrogels and the TME. In addition, the article highlights hydrogels' translational potential by outlining their roles in inflammation-associated biomarker detection, precision drug delivery systems, and in vivo compatibility evaluations. Recent advances in dynamic covalent hydrogels, DNA-based hydrogels, living hydrogels, and stimuli-responsive systems are critically reviewed to clarify the field's technological direction. Their integration with immunotherapy is particularly promising but raises concerns about long-term biosafety, degradation product toxicity, and immune compatibility. Despite their considerable promise for precisely modulating TME inflammation, hydrogels face persistent challenges that must be addressed to enable clinical potential. Overcoming these hurdles will require sustained multidisciplinary efforts. We further propose a stage-aware immunomodulatory framework, in which programmable hydrogels can coordinate mechanical, metabolic, and immune regulation according to the evolving biological state of the TME. Here, stage-aware does not imply a universal temporal hierarchy of TME remodeling, but rather refers to adaptive coordination of multiple regulatory modules according to tumor-specific biological states. This concept moves beyond single-pathway modulation and aligns with the emerging paradigm of "adaptive immunotherapy" that dynamically responds to TME evolution.