Abstract

ABSTRACT Malignant pleural effusion (MPE) portends poor prognosis in advanced cancer. Strategies that integrate potent tumor killing with immunosuppressive microenvironment reprogramming are crucial for the treatment of MPE. Studies show that irradiated tumor cell‐derived microparticles (RT‐MPs) possess natural tumor‐targeting cytotoxicity and innate immune activation properties. To further boost the tumoricidal effects of RT‐MPs, we developed innovative chemoradiotherapy‐integrated tumor cell‐derived microparticles (CR‐MPs) by loading RT‐MPs with chemotherapeutic agents, including methotrexate (MTX), monomethyl auristatin E (MMAE), or doxorubicin (DOX). CR‐MPs exhibited superior tumoricidal activity over both RT‐MPs and free drugs against a range of tumors. Specifically, MTX‐loaded CR‐MPs (CR‐MPs@MTX) triggered mitochondrial oxidative stress and immunogenic ferroptosis in tumor cells, while directly reprogramming macrophages toward the M1 phenotype and stimulating dendritic cells via cGAS‐STING/NF‐κB pathway activation. In murine MPE models, CR‐MPs effectively suppressed tumor progression, extended survival, and demonstrated favorable biosafety. When combined with immunotherapy, this approach achieved a cure rate of up to 70%, induced durable immunological memory, and retained efficacy against chemotherapy‐resistant tumors. This study establishes CR‐MPs as a novel platform with robust therapeutic efficacy against MPE, highlighting their translational potential as a precision concurrent chemoradiotherapy strategy for MPE management in clinical settings.