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

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. Here, a self-adjuvanting hydrogel is developed by co-mixing the arabinose-responsive bacteria and Man/HMPB(VE) nanoparticles (mannose-modified hollow mesoporous Prussian blue loaded with vitamin E). The prepared platform exhibits tumor-draining lymph node targeting checkpoint inhibition, immunogenic cell death, and self-reinforcing bacterial adjuvant through IL-15 expression, synergistically enhancing antitumor immunity. Thus, the hydrogel system is promising for cancer immunotherapy. image