NIR‐Triggered Methylgermanane Nanosheet‐Embedded Hydrogels Enable Cascade Dual‐Organelle Stress to Potentiate Cancer Immunotherapy

ABSTRACT The efficacy of photothermal therapy (PTT) mediated immunotherapy against tumor recurrence and metastasis is limited by inherent cellular thermoresistance and weak immune activation. To address this, we developed an accelerated immunomodulatory matrix reservoir (AIMR) integrating methylgermanane nanosheets (mGeNS) within an active Ca 2 + ‐crosslinked alginate hydrogel. As an emerging 2D material, mGeNS exhibits exceptional drug‐loading capacity and robust near‐infrared (NIR) photothermal conversion (efficiency > 60%). Importantly, the hydrogel matrix effectively shields these biodegradable nanosheets from premature in vivo clearance. Upon NIR irradiation, localized hyperthermia softens the hydrogel, triggering the co‐release of Ca 2+ and an mGeNS‐delivered immunogenic cell death (ICD) inducer (doxorubicin, DOX). This heat stimulation promotes intracellular Ca 2+ influx, causing mitochondrial dysfunction that downregulates thermoprotective heat shock proteins (e.g., HSP70), thereby sensitizing tumor cells and amplifying PTT‑mediated endoplasmic reticulum stress. Such a synergistic strategy boosts ICD accompanied by the release of numerous damage‐associated molecular patterns for dendritic cell maturation and CD8 + T cell activation. In murine bilateral tumor models, AIMR achieved > 80% local tumor suppression and a 2.43‐fold increase in abscopal immune memory over 60 days compared to surgery alone. By synergizing novel 2D mGeNS with active thermosensitive hydrogel, AIMR provides a dual‐organelle stress platform for durable photoimmunotherapy.