Targeting thetumor-associatedmacrophages(TAMs) with combinational drugs is a promising strategytoimproveimmunecheckpointblocking therapies.Tooptimize the synergetic effect of TAM-depletion, it is required for the delivery systemtodeliver multiple therapeutic drugstotheir corresponding action-sites. Herein, we design animmunemodulatingnanoparticle (IMNP) that can achieve a spatial control of the release sites of the drugstosynergistically deplete TAMs. IMNP has a core-shell structure in which the shell disassembles in acidic tumor microenvironment, resulting in the release of bindarit into the intercellular spacetoinhibit the recruitment of monocytes and exposing the core nCS(ALN)-Mantotrigger the apoptosis of TAMs. With this unique feature, systemic administration of IMNPtotumor-bearing mice effectively eliminated TAMs and altered the immunosuppressing tumor environment, which significantly improved the anti-tumor efficacy of anti-PD-1. Considering the antitumor efficacy of chemotherapy, irradiation and vascular-targeted therapies is also coun-teracted by TAMs, IMNP could be further developed in combination with these therapies for cancer treatment, implying the potential as a general applicationtoimprove the efficacy of cancer therapies.