Iron‐Tannic Acid Hydrogel Mediated Mild Photothermal Therapy Combined With Ferroptosis Enhances Anti‐Tumor Immunity in Colorectal Cancer

ABSTRACT Postoperative recurrence and metastasis are the primary causes of mortality in colorectal cancer (CRC). And its immunosuppressive tumor microenvironment (TME) often results in the poor response to immune checkpoint blockade (ICB). This study designed an injectable and adhesive tannic acid‐iron hydrogel for locally mild photothermal therapy (PTT, ≤ 45°C) and ferroptosis to prevent the postoperative recurrence and metastasis in combination with programmed death ligand 1 (PD‐L1) checkpoint blockade immunotherapy. First, this system was assembled from tannic acid (TA) and gelatin microspheres to form an injectable and adhesive hydrogel (Gel/TA). Subsequently, the metal‐polyphenol network (MPNs) was introduced via Fe 3+ ‐TA interactions, providing photothermal conversion and Fe 3+ release capabilities (Gel/TA/Fe 3+ ). Gel/TA/Fe 3+ hydrogels not only ablated tumor cells and induced immunogenic cell death (ICD) under near‐infrared (NIR) irradiation, but also elicited ferroptosis of both tumor cells and tumor‐associated macrophage (TAMs), resulting in dendritic cells (DCs) maturation, T‐cell infiltration and down‐regulation of ferroptosis‐sensitive M2‐type TAMs levels. Therefore, in cooperation with αPD‐L1, Gel/TA/Fe 3+ could not only evoke an immune response against the primary tumor, but also promote an abscopal effect against distant metastatic tumor. This work presented a novel material for CRC postoperative therapy via the synergistic effect of immediate tumor‐cell killing and enhanced immunotherapy.