Abstract 3866: Azvudine: An emerging immunomodulator in the treatment of cancer and viral infections

Abstract

Abstract Azvudine (FNC) is a nucleoside analog that has secured approval from the CDE in China for the treatment of both AIDS and COVID-19. In these contexts, it has showed remarkable efficacy and safety when taken orally. Typically, nucleoside analog drugs function by integrating into DNA and impeding DNA synthesis, evident in drugs like 5-FU, Capecitabine, Ara-C, and Gemcitabine. Furthermore, FNC has been reported to exhibit robust anti-tumor properties, curbing cell proliferation, initiating G1 and S phase arrests, and advancing apoptosis across various human cancer cell lines. Grounded in this mode of action, we have ascertained that the anti-tumor effects of FNC intricately align with the expression of deoxycytidine kinase (dCK) both in vitro and in vivo. Remarkably, our studies delved into the effects and underlying mechanisms of FNC in enhancing the tumor microenvironment within solid tumors. Our findings, stemming from cell-based assays and in vivo animal experiments, elucidate the following: 1. FNC can trigger immunogenic cell death (ICD) in tumor cells. This is evidenced by the surface presentation and liberation of damage-associated molecular patterns (DAMPs) such as Calreticulin, HSP70, HSP90, Annexin A1, and HMGB1, which in turn stimulate both innate and adaptive immune responses. 2. FNC substantially reduces the population of monocytic-myeloid derived suppressor cells (M-MDSC) and Polymorphonuclear-myeloid derived suppressor cells (PMN-MDSC) in the tumor microenvironment. Concurrently, it boosts the infiltration and proliferation of CD8+T, CD4+T and NK cells. This instigates the transformation of the tumor microenvironment from a 'cold' state to a 'hot' one, enhancing the synergistic effects of PD-1 when used in tandem with FNC. This mechanism was substantiated through a high proportion of MDSCs observed in H22 and CT-26 syngeneic models, and contrastingly, a low proportion in MC38 and LL/2 in vivo syngeneic models. Notably, every animal subjected to combined FNC and PD-1 treatment in the H22 and CT-26 in vivo models witnessed complete tumor regression. Given these revelations, there's a compelling argument that FNC monotherapy possesses immense potential as an anti-tumor agent. The potent anticancer effects of FNC in vitro and in vivo warrants further investigation of its anticancer potential as immunomodulator. Citation Format: Pan Li, Limin Jia, Zhaoyang Wang, Jinfa Du. Azvudine: An emerging immunomodulator in the treatment of cancer and viral infections [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3866.