Chronic inflammation in advanced tumors drives intense communication among tumor-resident immune cells, thereby weakening immunotherapy. Traditional anti-inflammatory treatments focus on alleviating chronic inflammation while neglecting the bone marrow-derived and T-cell dysfunction and scarcity that hinder the restoration of intercellular communication. To address this challenge, an inflammatory-induced inflammatory tumor inflammatory immune monitoring transfer hydrogel (TRANS) was developed to initiate an adaptive immune response mediated by intercellular communication. TRANS is induced by inflammatory diseases and releases celecoxib (CXB) to inhibit the COX-2/PGE2 pathway, thereby reprogramming tumor-associated macrophages and reducing tumor inflammation. Additionally, TRANS combines the FMS-like tyrosine kinase 3 ligand (Flt-3L) and the 4-1BB agonist (α-CD137), respectively, to recruit type 1 conventional dendritic cells (cDC1) and activate tumor-infiltrating T cells to restore immune monitoring. TRANS inhibits 87.50% and 88.74% of primary and secondary colorectal tumors, generating anti-tumor immune memory to resist tumor re-challenge, and significantly reducing lung and liver metastases. The re-challenge model shows that TRANS leads to the formation of anti-tumor immune memory. Single-cell RNA sequencing helps elucidate the mechanism of TRANS, which indicates that TRANS exerts an anti-tumor effect by optimizing the interaction between myeloid cells and T cells through the CXCL9/10-CXCR3/DPP4 pathway. When combined with immune checkpoint inhibitors, TRANS can better control colorectal cancer. This study provides a novel perspective on immunotherapy by rebalancing the inflammatory and immune dynamics. Innovation Points
01 The strategy upgrade from "anti-inflammatory" to "regulating immunity"
Unlike traditional methods that merely suppress chronic inflammation, this study innovatively combines the alleviation of inflammation with the restoration of immune cell functions. By targeting the COX-2/PGE2 pathway to reprogram macrophages, it not only alleviates immunosuppressive inflammation but also creates a favorable microenvironment for the subsequent recruitment and activation of immune cells.
02 Sequential delivery for immune cycle reconstruction
For the first time, COX-2 inhibitors were integrated with the immune modulator Flt-3L and the 4-1BB agonist onto a single inflammatory-responsive hydrogel platform. Utilizing the response characteristics of the hydrogel to the inflammatory microenvironment, the programmed release of the drugs was achieved: first anti-inflammatory reprogramming, then recruitment and activation of immune cells, completely restoring the immune cycle from antigen presentation to T cell killing.
03 Mechanism analysis focusing on intercellular communication
The study deeply revealed the mechanism of TRANS hydrogel, that is, by optimizing the CXCL9/10-CXCR3/DPP4 signaling axis between myeloid cells and T cells, restoring the effective interaction between them. This discovery provided new molecular-level insights into understanding how to reverse tumor immune suppression.
Journal Name: Bioactive Materials
Publication Date: March 12, 2026
DOI: 10.1016/j.bioactmat.2026.03.012
Research Team: Xinchao Li, Wangxian Fu, Hao Le, Rui Luo, Yingjie Li, Xiaorong Kou, Tao He, Liping Bai, Yangsong Xu, Jiayi Cao, Yixi Wang, Xinmao Yu, Peng Mi, Zichao Luo, Changyang Gong