Abstract
Metabolic reprogramming of the tumor microenvironment (TME) and poor immunogenicity are two of the challenges that cancer immunotherapies have to overcome for improved clinical benefits. Among various immunosuppressive metabolites that keep anti-tumor immunity in check, the tryptophan catabolite kynurenine (Kyn) is an attractive target for blockade given its role in mediating immunosuppression through multiple pathways. Here, we present a local chemo-immunometabolic therapy through injection of a supramolecular hydrogel concurrently releasing doxorubicin that induces immunogenic tumor cell death and kynureninase that disrupts Kyn-mediated immunosuppressive pathways in TME. The combination synergically enhances tumor immunogenicity and unleashes anti-tumor immunity. In mouse models of triple negative breast cancer and melanoma, a single low dose peritumoral injection of the therapeutic hydrogel promotes TME transformation toward more immunostimulatory, which leads to enhanced tumor suppression and extended mouse survival. In addition, the systemic anti-tumor surveillance induced by the local treatment exhibits an abscopal effect and prevents tumor relapse post-resection. This versatile approach for local chemo-immunometabolic therapy may serve as a general strategy for enhancing anti-tumor immunity and boosting the efficacy of cancer immunotherapies.