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

Abstract 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.