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Abstract Tumor‐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.

Abstract Coevolution of tumor cells and surrounding stroma results in protective protumoral environment, in which abundant vessel, stiff structure and immunosuppression promote each other, cooperatively incurring deterioration and treatment compromise. Reversing suchenvironment may transform tumors from treatment‐resistant to treatment‐vulnerable. However, effective reversion requires synergistic comprehensive regression of such environment under precise control. Here, the first attempt to collaboratively retrograde coevolutionary tumor environment to pre‐oncogenesis status, defined as tumor environment regression therapy, is made for vigorous immune response eruption by a switchable prune‐to‐essence nanoplatform (Pres) with simplified composition and fabrication process. Through magnetic targeting and multimodal imaging of Pres, tumor environment regression therapy is guided, optimized and accomplished in a trinity way: Antiangiogenesis is executed to rarefy vessels to impede tumor progression. By seizing the time, cancer associated fibroblasts are eliminated to diminish collagen and loosen the stiff structure for deep penetration of Pres, which alternately functioned in deeper tumors, forming a positive feedback loop. Through this loop, immune cell infiltration, immunosuppression mitigation and immunogenic cells death induction are all fulfilled and further escalated in the regressed environment. These transformations consequently unleashed systemic immune responses and generated immune memory against carcinoma. This study provides new insights intotreatment of solid tumors.