2ⁿᵈ Edition of the Cancer R&D World Conference 2026

Abstract

Background: Colorectal cancer (CRC) stands as a prevalent malignancy with significant morbidity globally, ranking as the third most common cancer and the second leading cause of cancer-related deaths. Despite advancements in early detection and treatment, the prognosis for CRC remains poor, emphasizing the urgent need for novel therapeutic strategies. Immunotherapy, especially immune checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4, has emerged as a promising treatment for CRC. However, most patients show limited responses to immunotherapy, necessitating improved predictive approaches and novel strategies to enhance immunotherapy efficacy across the broader CRC patient population.

Methods: In this study, we introduced three immune subtypes based on 45 immune-related signatures from diverse immune cells and pathways. The levels of immune infiltration and percentage of consensus molecular subtype (CMS) and microsatellite instability (MSI) were compared among the three subtypes. Subsequently, a robust predictive model was constructed through machine learning according to differentially expressed genes between high- and low-immune infiltration groups. The public and in-house cohort was used to validate the precision of the predictive model. Eventually, we performed drug screening using Connectivity map (CMap) database based on the top 100 up-and down-regulated genes between the high- and low-immune infiltration groups, and a series of in vivo and in vitro experiments was used to validate the positive effect of potential drug on anti-tumor immunity.

Results: Validation of this model across public and in-house cohort confirmed its high precision and reliability, and organoids from high-immune score patients exhibited more sensitive to immunotherapy. Furthermore, the IGF-1R inhibitor I-OMe-AG-538 (AG-538) was identified as a potent enhancer of antitumor immunity. In vitro and in vivo experiments indicated that AG-538 could promote the infiltration of multiple types of immune cells, activation of cytotoxic CD8+ T cells, and release of a series of cytokines and chemokines. Mechanistic investigations revealed it impairs DNA damage repair, triggering cGAS/STING-mediated IFN-I signaling within tumor cells. This signaling cascade increases tumor immunogenicity and refines the tumor immune microenvironment, thereby enhancing ICB treatment efficacy.

Conclusion: In summary, these findings present a novel predictive model for immune response and highlight the potential of AG-538 combined with anti-PD1 antibodies as a chemoimmunotherapeutic strategy. Assessing intratumoral IGF-1R expression may facilitate the prediction of the responses of patients with CRC to such therapies, paving the way for personalized treatment approaches.