Abstract Introduction: ACR-368 is a potent and selective CHK1/2 inhibitor with demonstrated durable clinical activity in a subset of patients with advanced solid tumors and is currently being evaluated as monotherapy and in combination regimens in Acrivon Therapeutics’ ongoing registrational-intent Phase 2 endometrial cancer clinical trial. Preclinical studies indicate that ACR-368 promotes anti-tumor immune responses, supporting its combination with immune checkpoint inhibitors (ICIs). Here, we investigate mechanisms of immune modulation by ACR-368 that contribute to antitumor efficacy. Results: In a syngeneic MC38 tumor model, ACR-368 monotherapy resulted in 74% tumor growth inhibition, while anti-PD-L1 treatment led to complete tumor regression in 2/8 mice. In contrast, combined ACR-368 and anti-PD-L1 treatment resulted in complete tumor regression in 7/8 mice and generated durable immune memory in 100% of mice, with protection persisting beyond 200 days after four sequential tumor rechallenges. Systematic depletion of immune cell subpopulations showed that the absence of either CD4+ or CD8+ T cells alone did not lead to tumor growth upon rechallenge, while co-depletion of both resulted in tumor formation, indicating that immune memory is driven by adaptive immune responses. In vitro, ACR-368 treatment of MC38 cells robustly activated innate immune signaling and nucleic acid sensing pathways. In vivo, quantitative immunofluorescence (IF) of MC38 tumors following short-term treatment with ACR-368, anti-PD-L1, or with the combination demonstrated CHK1/2 target engagement, activation of innate immunity, and induction of apoptosis. IF analysis of M1/M2 macrophage polarization markers in MC38 tumor tissues revealed a pronounced shift toward a pro-inflammatory M1 phenotype primarily driven by ACR-368 and further enhanced by combination with anti-PD-L1. Combination therapy also activated CD8+ T and NK cells and led to the downregulation of markers associated with T-cell exhaustion and ICI therapy resistance. Conclusion: ACR-368 synergizes with PD-L1 blockade by activating adaptive and innate immune pathways, resulting in potent tumor regression and durable immune memory. These data provide a strong mechanistic rationale for clinical evaluation of ACR-368 in combination with ICIs in tumors selected for sensitivity to these agents. Citation Format: Amira Elbakry, Taronish Dubash, Joelle Baddour-Sousounis, Jessica Hopkins, Subodh Kumar, Ahmed Youssef, Yingchun Spring Liu, Kate Rappard, Calvin Yang, Ignacio Arribas Diez, Marc Isaksson, Luka Romero, Zachary Best, Nina Lipjankic, Sofija Skoric, Courtney Cooper, Emma Ahrman, Valentina Siino, Portia Lombardo, Corey Xu, Magnus E. Jakobsson, Helen Nilsson, Lei Shi, Ayesha Murshid, Michail Shipitsin, Joon Jung, David Proia, Kristina Masson, Peter Blume-Jensen. ACR-368 synergizes with PD-L1 blockade by coordinated activation of adaptive and innate immunity pathways to achieve robust anti-tumor efficacy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB152.
Elbakry et al. (Fri,) studied this question.