Hematopoietic　progenitor　kinase　1　(HPK1),　a　negative　regulator　of　the　TCR　signaling　pathway,　has　emerged　as　an　attractive　drug　target　for　tumor　immunotherapy.　Herein,　we　report　the　discovery　of　a　series　of　pyrazine-based　HPK1　PROTAC　degraders.　The　representative　compound　10m　demonstrated　potent　and　sustained　HPK1　degradation　(DC50　=　5.0　±　0.9　nM;　Dmax　≥　99%).　Upon　TCR　activation,　10m　significantly　inhibited　SLP76　phosphorylation　and　enhanced　ERK　pathway　activation　through　degrading　HPK1,　thereby　stimulating　IL-2　and　IFN-γ　release.　Furthermore,　10m　exhibited　the　ability　to　overcome　the　immunosuppressive　effects　imposed　by　PGE2,　NECA　or　TGF-β.　Notably,　orally　administration　of　10m　alone　efficaciously　inhibited　tumor　growth　in　an　MC38　syngeneic　mouse　model.　Moreover,　10m　achieved　a　superior　antitumor　effect　when　combined　with　PD-1　blockade,　suggesting　the　complementarity　between　the　two　treatment　modalities.　Overall,　this　work　provides　promising　lead　compounds　for　the　clinical　development　of　HPK1　PROTACs　as　small-molecule　therapeutics　in　tumor　immunotherapy.