Chronic inflammation in intermediate/advanced tumors drives burdensome protumor immune cell communication, thereby weakening immunotherapy. Conventional anti-inflammatory therapies focus on alleviating chronic inflammation whereas ignore dysfunction and scarcity of myeloid and T cells, which hinder their intercellular communication restoration. To address the dilemma, an inflammatory condition-triggered protumor inflammation-immunosurveillance shift hydrogel (TRANS) is developed to initiate adaptive immune responses mediated by intercellular communication. Triggered by inflammatory conditions, TRANS releases celecoxib (CXB) to inhibit the COX-2/PGE2 pathway, thereby reprogramming tumor-associated macrophages and mitigating protumor inflammation. Furthermore, TRANS incorporates FMS-like tyrosine kinase 3 ligands (Flt-3L) and 4-1BB agonists (α-CD137) to respectively recruit type 1 conventional DC (cDC1) and revitalize tumor-infiltrating T cells, to rejuvenate immunosurveillance. TRANS inhibits 87.50% and 88.74% of primary and secondary colorectal tumors, generates antitumor immune memory to resist tumor rechallenge, and significantly reduces lung and liver metastases. Rechallenge model shows TRANS leads to antitumor immune memory formation. Single-cell RNA sequencing is preform to elucidate the mechanism of TRANS, which exhibits that TRANS exerts antitumor effects by optimizing the crosstalk between myeloid cells and T cells via CXCL9/10-CXCR3/DPP4. TRANS further gains better control of colorectal cancer when combined with immune checkpoints inhibitors. This study offers a novel perspective on immunotherapy by rebalancing inflammation-immunity dynamics. Immunosurveillance succumbs in the dynamic game with chronic inflammation under the natural progression of cancer, thereby driving the deterioration of tumor. Hence, a chronic inflammation-responsive hydrogel (TRANS) was designed to simultaneously alleviate chronic inflammation and enhance immunosurveillance through myeloid-T cell crosstalk, thereby improving the local immune microenvironment and triggering systemic immune responses. TRANS demonstrated effective primary tumor suppression and metastases control. When combined with immune checkpoint inhibitors, TRANS achieved tumor regression. • Hydrogel scaffold exhibits adjuvant-like effects for DC and macrophage activation. • TRANS restores myeloid-T cell crosstalk and drives immune niches formation. • TRANS achieves the shift from chronic inflammation to immunosurveillance. • TRANS effectively suppresses lung and liver metastases of colorectal cancer. • Tumor-free status was maintained in a subset of mice for approximately 40 days after TRANS treatment.
Li et al. (Thu,) studied this question.
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