Tumor Microenvironment-Responsive Smart Hydrogel: Engineering Next-Generation in situ Tumor Vaccines for Synergistic Tumor Immunotherapy.

Tumor vaccines represent a promising approach for tumor immunotherapy, yet their clinical translation is greatly impeded by cumbersome antigen screening, poor adaptation to tumor heterogeneity, inefficient antigen presentation, and insufficient immune activation. Tumor microenvironment (TME)-responsive smart hydrogels have emerged as advanced platforms for constructing next‑generation whole‑cell tumor vaccines, featuring tunable microstructures, spatiotemporally controlled cargo release, and excellent in situ TME adaptability. These hydrogel‑based vaccines directly employ intact tumor tissues as broad‑spectrum antigen reservoirs, avoiding complex antigen isolation and identification to effectively overcome tumor heterogeneity. Hydrogel‑based vaccines enable stimuli‑responsive sequential release of antigens, adjuvants, and bioactive factors, precisely modulating immune cascades to elicit robust systemic antitumor immunity against tumor growth, invasion, and metastasis. This review systematically summarizes the design principles, fabrication strategies, and immunomodulatory mechanisms of TME‑responsive hydrogel‑based whole‑cell vaccines, highlights their structure-efficacy relationships, and discusses key challenges in clinical translation. Furthermore, this review proposes future directions to guide the rational development of high‑performance immunotherapeutic formulation with strong clinical potential for personalized tumor treatment.