Breaking the Tumor Chronic Inflammation Balance with a Programmable Release and Multi‐Stimulation Engineering Scaffold for Potent Immunotherapy

Abstract

AbstractTumor‐associated chronic inflammation severely restricts the efficacy of immunotherapy in cold tumors. Here, a programmable release hydrogel‐based engineering scaffold with multi‐stimulation and reactive oxygen species (ROS)‐response (PHOENIX) is demonstrated to break the chronic inflammatory balance in cold tumors to induce potent immunity. PHOENIX can undergo programmable release of resiquimod and anti‐OX40 under ROS. Resiquimod is first released, leading to antigen‐presenting cell maturation and the transformation of myeloid‐derived suppressor cells and M2 macrophages into an antitumor immune phenotype. Subsequently, anti‐OX40 is transported into the tumor microenvironment, leading to effector T‐cell activation and inhibition of Treg function. PHOENIX consequently breaks the chronic inflammation in the tumor microenvironment and leads to a potent immune response. In mice bearing subcutaneous triple‐negative breast cancer and metastasis models, PHOENIX effectively inhibited 80% and 60% of tumor growth, respectively. Moreover, PHOENIX protected 100% of the mice against TNBC tumor rechallenge by electing a robust long‐term antigen‐specific immune response. An excellent inhibition and prolonged survival in PHOENIX‐treated mice with colorectal cancer and melanoma is also observed. This work presents a potent therapeutic scaffold to improve immunotherapy efficiency, representing a generalizable and facile regimen for cold tumors.