Although ICIs have demonstrated robust and durable responses in several solid tumor types, most patients display primary or secondary resistance, often attributed to an immunosuppressive microenvironment and/or T-cell exhaustion. Thus, there is a high unmet need for agents that can overcome ICI resistance to improve patient outcomes. HPK1 negatively regulates T-cell activation/proliferation, promotes T-cell exhaustion, and modulates activation of other immune cell types through kinase and less well-defined scaffolding activity. Degradation of HPK1 by ARV-6723, a potent, oral PROteolysis TArgeting Chimera (PROTAC), has the potential to induce broad immunomodulatory changes and overcome multiple mechanisms of ICI resistance, restoring T-cell activation and attenuating T-cell exhaustion. ARV-6723 (5 or 30 mg/kg orally once daily) was compared with an anti-programmed death-1 (PD-1) antibody (10 mg/kg intravenously [IV] twice weekly [BIW]) alone or combined with an anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody (10 mg/kg IV BIW) in syngeneic mouse tumor models of ICI resistance (a murine-derived lung cancer cell line chronically treated in vitro with interferon-gamma [LLC1-IFNgamma] to model T-cell dysfunction/exhaustion and Kras LSL-G12D/+ ;Trp53 LSL-R172H/+ ;Pdx1-Cre;Rosa26 YFP/YFP [KPCY] to model T-cell exclusion/low T-cell infiltration). Immunomodulatory activity was characterized by multicolor flow cytometry and by whole transcriptome and peripheral cytokine analyses. In the LLC1-IFNgamma model, ARV-6723 (5 and 30 mg/kg) induced significant tumor growth inhibition (TGI) of 27% ( P <0.01) and 57% ( P <0.001), respectively, whereas anti-PD-1 antibody alone or combined with anti-CTLA-4 antibody did not yield significant TGI (2% and 13%, respectively). In the KPCY model, ARV-6723 (30 mg/kg) induced TGI of 89% ( P <0.01), comparable to the anti-PD-1/anti-CTLA-4 antibody combination (83%; P <0.05) and superior to anti-PD-1 antibody alone (28%). Preliminary mechanistic analysis revealed differential immunomodulatory effects in the periphery with ARV-6723 that were not seen with anti-PD-1 antibody alone or combined with anti-CTLA-4 antibody, eg, increased effector/memory T cells, increased natural killer (NK) cells, and correlative cytokine changes (decreased immunosuppressive cytokine interleukin [IL]-10 and increased proinflammatory cytokines IL-5 and keratinocyte-derived chemokine). ARV-6723 demonstrated greater antitumor activity and proinflammatory, immunomodulatory effects (including increased NK and T cell populations) than single-agent or combination ICI in preclinical models of ICI resistance. These data highlight the potential for ARV-6723 to overcome ICI resistance, supporting its future investigation alone or in combination with ICIs in patients with solid tumors.