Immunosuppressive-responsive hydrogel for self-regulated drug release and tumor microenvironment reprogramming

The tumor immunosuppressive microenvironment (TIME) critically suppresses antitumor immunity and fosters tumor growth and metastasis, leading to treatment resistance and poor prognosis. Inhibition of the upstream immunosuppressive regulator transforming growth factor-β (TGF-β) is an effective approach but systemic blockade should be avoided. To address this, an intelligent and injectable thermo-responsive hydrogel delivery system (LY@CNSG) constructed from cyclodextrin nanosponges and poly(N-isopropylacrylamide) was developed, in response to immunosuppressive prostaglandin E2 (PGE2) levels for autonomously controlling the release of LY2109761 (LY, a TGF-β inhibitor) based on competitive host-guest interaction. In triple-negative breast cancer models, photodynamic therapy combined with LY@CNSG significantly inhibited tumor growth and lung metastasis while enhancing antitumor immune activity. Furthermore, by integrating nitric oxide (NO)-responsive fluorescent probes, we created an integrated hydrogel platform, CYNH₂-LY@CNSG, for simultaneous immunomodulator delivery and immune signaling molecule monitoring, providing a novel insight for biomarker monitoring and a more precise immunotherapy paradigm.