An on-site cascading vaccine breaks tumor immune evasion and elicits systemic immunity

Tumor cells evade immunosurveillance through a defense system conceptualized as camouflage, coercion, and cytoprotection. Therapeutic success requires simultaneous targeting of them all to restore antitumor immunosurveillance. Furthermore, the induction of effective antitumor immunity requires the efficient transition of hierarchical cascaded immune response processes. Hence, an on-site cascading vaccine (SAGE) was developed to simultaneously break the camouflage, coercion, and cytoprotection of tumor immune evasion to restore immunosurveillance and elicit systemic immunity. After intravenous administration, SAGE effectively accumulates at the tumor site and is precisely activated by irradiation. Subsequently, SAGE promotes on-site immunogenic tumor cell death to prompt dendritic cell recruitment and maturation to break camouflage and initiate innate immunity. This innate immunity is then transitioned to adaptive immunity through the breakdown of coercion by reinvigorating effector T cells and draining immunosuppressive cells. Moreover, SAGE boosts effector immune cell infiltration to break cytoprotection and amplify adaptive immunity to systemic immune responses. Consequently, SAGE simultaneously breaks the defense system and improves the strength of hierarchical immune response processes, providing new insights for immunotherapies that revitalize immunosurveillance and elicit systemic immunity to curb primary, recurrent, and metastatic tumors.