Genetically Engineered Light‐Responsive In Situ Hydrogels for Immunomodulation and Multimodal Therapy in Metastatic Triple‐Negative Breast Cancer

Abstract Triple‐negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer, known for its early onset, strong metastatic tendencies, and poor prognosis. Conventional treatments, including chemotherapy and immunotherapy, often face challenges such as limited efficacy, adverse side effects, and high recurrence rates. To address these limitations, a family of tri‐block chimeric proteins, cysteine‐tagged silk‐elastin‐like proteins (cSELPs), is designed to form responsive in situ hydrogels for treating late‐stage and metastatic TNBC. These cSELPs are de novo designed to integrate multiple functional protein motifs, including a photothermal agent binding motif, silk‐inspired crosslinking motifs, and elastin‐like thermo‐responsive motifs. This unique sequence design enables the cSELP hydrogels to exhibit in situ gelation, photothermal responsive release of chemotherapeutic agent doxorubicin and immune checkpoint inhibitor anti‐PD‐L1, and antibacterial properties, leading to effective tumor microenvironment remodeling. By promoting immunogenic cell death and stimulating immune activation, this approach converts immunosuppressive “cold” tumors into immunologically active “hot” tumors. The cSELP hydrogel system demonstrates potent therapeutic efficacy against both primary and metastatic TNBC while maintaining excellent biocompatibility and long‐term safety. This protein material platform offers an innovative strategy to reshape the tumor microenvironment and combine multimodal treatments into a single biocompatible system, highlighting its potential for clinical translation.