Effective antitumor activity of chemotherapy can be counterbalanced by efferocytosis by generating immunosuppressive tumor microenvironment. Targeted blocking efferocytosis at an early stage of cell apoptosis exerts promising benefits on achieving improved chemotherapy, but it appears to have considerably limited outcome due to the uncontrolled release of chemotherapeutic and efferocytosis inhibitors. Herein, a mesoporous silica nanoparticle (MSN)-based nanoconfined assembly strategy is created to co-deliver chemotherapeutic drug doxorubicin (DOX) and efferocytosis inhibitor BMS777607 (BMS) for efficient cancer chemo-immunotherapy. DOX and BMS self-assembly forms nanoparticulate crystal confined within the mesopore of tailor-made MSN, and nanocrystal-encapsulated MSN (denoted as SC-MSN@D/B) enables synchronized drug release behaviors, which is beneficial for efferocytosis blockade at the early stage of apoptosis. Consequently, intravenous injection of SC-MSN@D/B leads to a synergistic inhibition of tumor growth in colon and breast cancer models through inducing a stimulatory immune response, from the secretion of pro-inflammatory cytokines to the inhibition of tumor associated macrophages and regulatory T cells infiltration. The combination of SC-MSN@D/B with checkpoint blockade inhibitors further amplifies the therapeutic effect of on tumor growth and pulmonary metastasis of orthotopic 4T1 breast tumors, and establishes long-term immune memory, offering tremendous potential for a combined efferocytosis-blocking strategy in cancer chemo-immunotherapy.