Background:　Immune　checkpoint　blockers　(ICBs)　are　revolutionized　therapeutic　strategies　for　cancer,　but　most　patients　with　solid　neoplasms　remain　resistant　to　ICBs,　partly　because　of　the　difficulty　in　reversing　the　highly　immunosuppressive　tumor　microenvironment　(TME).　Exploring　the　strategies　for　tumor　immunotherapy　is　highly　dependent　on　the　discovery　of　molecular　mechanisms　of　tumor　immune　escape　and　potential　therapeutic　target.　Kruppel-like　Factor　5　(KLF5)　is　a　cell-intrinsic　oncogene　to　promote　tumorigenesis.　However,　the　cell-extrinsic　effects　of　KLF5　on　suppressing　the　immune　response　to　cancer　remain　unclear.　Methods:　We　analyzed　the　immunosuppressive　role　of　KLF5　in　mice　models　transplanted　with　KLF5-deleted/overexpressing　tumor　cells.　We　performed　RNA　sequencing,　immunohistochemistry,　western　blotting,　real　time-PCR,　ELISA,　luciferase　assay,　chromatin　immunoprecipitation　(ChIP),　and　flow　cytometry　to　demonstrate　the　effects　of　KLF5　on　CD8+　T　cell　infiltration　and　related　molecular　mechanism.　Single-cell　RNA　sequencing　and　spatial　transcriptomics　analysis　were　applied　to　further　decipher　the　association　between　KLF5　expression　and　infiltrating　immune　cells.　The　efficacy　of　KLF5/COX2　inhibitors　combined　with　anti-programmed　cell　death　protein　1　(anti-PD1)　therapy　were　explored　in　pre-clinical　models.　Finally,　a　gene-expression　signature　depending　on　KLF5/COX2　axis　and　associated　immune　markers　was　created　to　predict　patient　survival.　Results:　KLF5　inactivation　decelerated　basal-like　breast　tumor　growth　in　a　CD8+　T-cell-dependent　manner.　Transcriptomic　profiling　revealed　that　KLF5　loss　in　tumors　increases　the　number　and　activated　function　of　T　lymphocytes.　Mechanistically,　KLF5　binds　to　the　promoter　of　the　COX2　gene　and　promotes　COX2　transcription;　subsequently,　KLF5　deficiency　decreases　prostaglandin　E2　(PGE2)　release　from　tumor　cells　by　reducing　COX2　expression.　Inhibition　of　the　KLF5/COX2　axis　increases　the　number　and　functionality　of　intratumoral　antitumor　T　cells　to　synergize　the　antitumorigenic　effects　of　anti-PD1　therapy.　Analysis　of　patient　datasets　at　single-cell　and　spatial　resolution　shows　that　low　expression　of　KLF5　is　associated　with　an　immune-supportive　TME.　Finally,　we　generate　a　KLF5/COX2-associated　immune　score　(KC-IS)　to　predict　patient　survival.　Conclusions:　Our　results　identified　a　novel　mechanism　responsible　for　KLF5-mediated　immunosuppression　in　TME,　and　targeting　the　KLF5/COX2/PGE2　axis　is　a　critical　immunotherapy　sensitizer.