Abstract

Surgery is the mainstay of treatment for patients with solid tumors. However, the intricate inflammatory and immunosuppressive tumor microenvironment after surgery is recognized as a primary cause of tumor recurrence and metastasis. Here, we design and construct an in situ injectable therapeutic hydrogel encapsulating 1-methyl-d-tryptophan (1-d-MT), a small-molecule competitive inhibitor of indoleamine 2,3-dioxygenase, and meloxicam, a selective inhibitor of cyclooxygenase-2 (Ge1MT/Mel hydrogel) to prevent postoperative tumor metastasis and relapse. In this hydrogel system, 1-d-MT increases cytotoxic T lymphocytes and decreases regulatory T cells, thereby reversing the tumor immune tolerance microenvironment, while released meloxicam reduces inflammation caused by postoperative trauma via the COX-2/PGE2 pathway. When delivered into the resected tumor cavity, the hydrogel system mimics a “hot” tumor-immunity niche to attack residual tumor cells and significantly suppresses the postoperative recurrence of colorectal cancer. In the model of postoperative breast cancer and colorectal cancer recurrence and metastasis, the Ge1MT/Mel hydrogel substantially reduces the volume of recurrent tumors and demonstrates 85.1% and 66.7% inhibition rates of metastases, respectively. Importantly, the Ge1MT/Mel hydrogel markedly stimulates a potent antitumor immune response in the cancer lesion microenvironment, increasing antitumor immune cells including CD8+ T cells, as well as elevating antitumor cytokines such as interferon-γ. Overall, combination immunotherapy via the Ge1MT/Mel hydrogel after surgery represents a promising strategy to minimize residual tumor burden and reduce recurrence risk following tumor resection.