Localized chemotherapy through metabolic stabilization and in situ gelation for ratio-locked delivery to maximize cytotoxicity and trigger immune responses

Chemotherapy is an important strategy in cancer treatment, and harnessing the immunomodulatory potential of chemotherapeutic agents presents novel opportunities for chemoimmunotherapy. The oxaliplatin (OXA) and gemcitabine (GEM) regimen, a clinically established protocol for solid tumors, primarily exerts therapeutic effects through synergistic cytotoxicity, with emerging evidence supporting its ancillary immune-modulating properties. However, intravenous administration is frequently associated with systemic toxicity and impedes precise control of drug ratios within the tumor. Furthermore, GEM undergoes rapid enzymatic degradation by cytidine deaminase (CDA), which is highly expressed in both tumor cells and intratumoral microbiota, compromising its efficacy and disrupting the therapeutic equilibrium with OXA. To overcome these limitations, we developed a sodium alginate (ALG)-based in situ hydrogel system for co-delivery of OXA, GEM, and the CDA inhibitor cedazuridine (CDZ) in a ratio-locked design. Following intratumoral injection, ALG underwent Ca 2+ -triggered gelation, facilitating localized drug retention and sustained synchronized release to mitigate off-target toxicity. CDZ enhanced the metabolic stability of GEM, maintaining the optimal GEM/OXA ratio. Concurrently, beyond cytotoxic synergy, OXA-triggered immunogenic cell death and GEM-driven regulatory T-cell depletion collectively enhance antitumor immunity. This ratio-locked localized delivery platform, integrated with metabolic stabilization, enables precise regimen control to achieve safe and potent chemoimmunotherapy.