Self‐Adjuvanting Bacteria Hydrogel for SHP1 Checkpoint Inhibition in Tumor‐Draining Lymph Nodes to Enhance Cancer Immunotherapy

Abstract Despite recent advances in immunotherapy, its efficacy remains constrained by the absence of immune coordination. Especially, the interplay between tumor‐draining lymph nodes (TDLNs) and tumors is frequently disregarded. Here, a self‐adjuvanting hydrogel capable of eliciting a powerful and sustained immune response is developed. Briefly, the engineered arabinose response bacteria (ARB) expressing IL‐15 and mannose‐modified hollow mesoporous Prussian blue nanoparticles (NPs) loaded with vitamin E (Man/HMPB(VE), MHV) are mixed with arabinose hydrogel (AraGel), forming the system designated as AraGel@ARB/MHV (AAM). Employing mild photothermal therapy mediated by MHV, immunogenic cell death (ICD) triggers the release of tumor‐associated antigens. Subsequently, Man‐modified NPs target TDLNs and release VE, which suppresses the checkpoint Src homology region 2 domain‐containing phosphatase‐1 (SHP1) in dendritic cells, thereby enhancing antigen presentation and T cell activation. Meanwhile, IL‐15 expression of ARB(IL‐15) induced by AraGel degradation enables ARB to serve as an enhanced adjuvant in a self‐adjuvanting manner, working synergistically with ICD and TDLN reprogramming to promote cytotoxic T lymphocytes activation. The hydrogel system efficiently suppresses tumor growth by eliciting prolonged and powerful immunotherapy in an orchestrated manner. Overall, the self‐adjuvanting hydrogel holds great potential for cancer immunotherapy.