A losartan-laden thermosensitive hydrogel scaffold to boost tumor chemo-immunotherapy via remodeling tumor mechanical microenvironment

Currently, the groundbreaking progress of immune checkpoint inhibitors has benefited patients with various types of tumors. However, the efficacy of these inhibitors is constrained by the tumor immune-suppressive microenvironment. Furthermore, the hypoxia mediated by intratumoral vascular compression further weakens the anti-tumor immune response within the tumor. Herein, we have meticulously developed a drug-sustained-release scaffold that contains three drug components of oxaliplatin, losartan, and immune checkpoint inhibitor (anti-PD-L1), structured with a thermosensitive hydrogel F127 that can gel in situ upon triggering at body temperature. Oxaliplatin, an effective chemotherapeutic agent, can induce immunogenic cell death in tumor, effectively alleviating the tumor immune-suppressive microenvironment. Meanwhile, losartan potassium, a clinical antihypertensive drug, can reduce tumor stroma, lower tumor solid stress, and relieve intratumoral vascular compression, thereby improving tumor hypoxia. The anti-PD-L1 is a widely used immune checkpoint inhibitor and can precisely block the binding of PD-L1 to PD-1, activating T cell-mediated anti-tumor immune responses. The constructed F127@Oxpt-Los-aPDL1 scaffold triggers a potent anti-tumor immune response, achieving outstanding tumor suppression effects and even induces a powerful abscopal effect, effectively inhibiting the growth of distant tumors. This research presents a novel combination treatment strategy aimed at enhancing the efficacy of immune checkpoint inhibition therapy in stroma-rich tumors.

Immunogenic cell death; Sustained-release thermosensitive scaffold; Tumor immunotherapy; Tumor solid stress; Vascular compression.