Thermosensitive spray-gel oxaliplatin delivery system for antitumor efficacy and mechanistic study in a mouse subcutaneous xenograft model.

Postoperative recurrence of colorectal cancer remains a major challenge to patient prognosis due to the residual tumor cells and an immunosuppressive tumor microenvironment. In this study, a thermosensitive in situ sprayable gel (iSGel@OXA) was developed for localized the delivery of oxaliplatin (OXA) after surgery. The gel exhibited excellent sprayability, rapid gelation, strong tissue adhesion, mechanical stability and sustained drug release. In a mouse model of incomplete colorectal cancer resection, iSGel@OXA significantly suppressed tumor regrowth and prolonged survival. Mechanistic investigations revealed that the drug-loaded gel achieved synergistic regulation of CD4 T cells and LY6C myeloid-derived suppressor cells, specifically upregulated TNF-α to remodel the cytokine network, and inhibited the TGF-β signaling pathway. Furthermore, the sustained-release gel facilitated a more precise and efficient anti-tumor strategy by promoting apoptosis, inducing immunogenic cell death (ICD), and orchestrating profound changes in key intra-tumoral pathways and networks, such as Stat1-Src and the complement system. Collectively, this study provides a strong theoretical rationale and technical foundation for the application of thermosensitive hydrogel-mediated local chemotherapy-immunotherapy in postoperative colorectal cancer treatment.