ACR-368通过协调激活适应性和先天性免疫通路与PD-L1阻断产生协同作用，实现强效抗肿瘤疗效

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.