Catalytical nanogels reprogram immunosuppressive metabolic networks for activatable cancer photo-immunotherapy

Metabolic dysregulation is a hallmark of cancer, making the modulation of these pathways an attractive therapeutic strategy; however, its clinical efficacy is often undermined by compensatory metabolic networks and inefficient tumor targeting effects. Here, we developed catalytical nanogels reprogramming immunosuppressive metabolic networks for activatable cancer photo-immunotherapy. The nanogels (abbreviated as OMST) were synthesized by crosslinking the oxidized hyaluronic acid with an methylthioadenosine (MTA)-catabolizing enzyme (methylthioadenosine phosphorylase: MTAP), an MTA-anabolism inhibitor (spermidine synthase inhibitor: SRMi), and the photosensitizer (TAPP) to form acid-cleavable imine bonds. Only in the acidic tumor microenvironment (TME), OMST was specifically disassociated to activate MTAP and SRMi, resulting in a synergistic two-side metabolic reprogramming for promoting MTA degradation and inhibiting its production, respectively. This two-side MTA depletion strategy reprogrammed the immunosuppressive TME, thus inhibiting protumorigenic M2 macrophages, promoting the antigen presentation of dendritic cells, and enhancing the proliferation of cytotoxic T lymphocytes. Upon localized photoirradiation, TAPP generated reactive oxygen species to induce immunogenic cell death, thereby synergizing with MTA metabolic reprogramming to reinvigorate antitumor immunity. Both in vitro and in vivo experiments demonstrated that OMST could effectively suppress tumor growth, metastasis, and recurrence. Thus, this study proposed a precise and multidimensional metabolic reprogramming strategy towards cancer therapy.