An　immunosuppressive　tumor　microenvironment　(TME)　with　inadequate　and　exhausted　tumor-infiltrating　cytotoxic　lymphocytes　and　abundant　cellular　immunosuppressors　is　the　major　obstacle　responsible　for　the　poor　efficacy　of　PD-1/PD-L1　(programmed　cell　death　1　and　its　ligand　1)　immune　checkpoint　blockade　(ICB)　therapy.　Herein,　a　Janus　silica　nanoparticle　(JSNP)-based　immunomodulator　is　explored　to　reshape　the　TME　for　boosting　the　therapeutic　outcomes　of　αPD-L1　therapy.　The　designed　JSNP　has　two　distinct　domains,　namely,　an　ultra　pH-responsive　side　(UPS),　which　could　encapsulate　PI3Kγ　inhibitor　IPI549　in　the　pore　structure,　and　a　polycation-grafted　intra-glutathione　(GSH)-sensitive　side　(IGS),　which　could　absorb　CXCL9　cDNA　on　the　surface.　The　final　IPI549@UPS-IGS-PDMAEMA@CXCL9　cDNA　(IUIPC)　could　release　IPI549　in　weak　acid　TME　to　target　myeloid-derived　suppressor　cells　(MDSCs)　to　reverse　negative　immunoregulation　and　then　release　CXCL9　cDNA　in　tumor　cells　with　abundant　GSH　for　sustained　CXCL9　chemokine　expression　and　secretion　to　improve　cytotoxic　lymphocyte　recruitment　signals,　thereby　jointly　restoring　tumor　sensitivity　to　PD-1/PD-L1　ICB　therapy.　As　expected,　the　IUIPC-mediated　TME　remodeling　during　αPD-L1　therapy　significantly　ameliorated　TME　immunosuppression,　as　well　as　induced　potent　systemic　antitumor　immune　responses,　which　ultimately　achieved　a　robustly　boosted　antitumor　efficacy　proven　by　remarkable　suppression　of　primary　tumor　growth,　obvious　prevention　of　tumor　recurrence,　and　significant　regression　of　abscopal　tumors.　Hence,　the　IUIPC-mediated　TME-regulating　strategy　provides　an　enormous　perspective　for　the　improvement　of　PD-1/PD-L1　ICB　therapy.　©　2023　American　Chemical　Society.