Abstract 7306: Selective and novel ALDH1 inhibitor enhances immune checkpoint blockade therapy in preclinical models of MSS colorectal cancer

Abstract Colorectal cancer (CRC) is the second leading cause of cancer-related deaths globally and the third most frequently diagnosed cancer type, according to the Global Cancer Observatory. While the emergence of immune-checkpoint inhibitors (ICI) in the past decade has transformed cancer treatment paradigms, their efficacy in CRC is limited, particularly in the microsatellite-stable (MSS) subtype, which constitutes 85% of cases. MSS CRC is characterized by a low mutation burden and an immunosuppressive tumor microenvironment (TME), resulting in poor responsiveness to ICIs. Recent studies have identified elevated ALDH1 expression and its enzymatic products in MSS tumors, with retinoic acid (RA) produced by ALDH1 playing a pivotal role in fostering an immunosuppressive TME. This RA-mediated immunosuppression arises not only from tumor cells but also from tumor-associated immune cells, such as M2 macrophages and myeloid-derived suppressor cells (MDSCs), both of which exhibit high ALDH1 activity. Using syngeneic mouse models of MSS CRC, including MC38-CEA and CT26 cell lines, we evaluated the therapeutic potential of combining ABD0171, a selective ALDH1 inhibitor (ALDH1i), with anti-PD-1 therapy. Our findings reveal that ABD0171 significantly enhances the efficacy of anti-PD-1 therapy, leading to improved survival outcomes in MSS CRC models. This synergistic effect is associated with substantial alterations in the TME immune landscape, including an increase in pro-inflammatory M1 macrophages and reductions in both M2 macrophages and regulatory T cells (Tregs). Mechanistically, ALDH1 inhibition significantly reduces intratumoral RA levels, disrupting a key pathway responsible for the differentiation of immunosuppressive macrophages from monocytes. Ongoing studies are exploring the molecular mechanisms underlying these effects. Overall, our work underscores the potential of selective ALDH1 targeting as a strategy to overcome immunotherapy resistance in MSS CRC, offering new therapeutic opportunities for patients with this challenging cancer subtype. Citation Format: Akinchan Kumar, Andrada Constantinescu, Ismail Ceylan, Mileidys Perez-Alea, Bassam Janji. Selective and novel ALDH1 inhibitor enhances immune checkpoint blockade therapy in preclinical models of MSS colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7306.