An Oral PROTAC Targeting HPK1 Degradation Potentiates Anti‐Solid Tumor Immunity

Hematopoietic progenitor pinase1 (HPK1) knockout has been identified as an efficient route to enhance anti-tumor immune response. Here, this work develops an oral proteolysis targeting chimera (PROTAC) targeting HPK1 to efficiently and selectively degrade HPK1 to augment immunotherapeutic outcomes. In a postoperative tumor model of human cervical cancer in NSG mice, the orally-administrated PROTAC can reach tumors, down-regulate HPK1 levels in locally-administrated CAR-T cells, and promote their efficiency in inhibiting solid tumor recurrence, achieving 50% partial response (PR) and 50% complete response (CR). In addition, oral administration of PROTAC can amplify the suppression capability of the anti-PD-L1 antibody on the growth of CT26 solid tumors in BALB/c mice by promoting the infiltration of CD45-positive immune cells from 0.7% to 1.5% and CD3-positive T cells from 0.2% to 0.5% within the tumors.