Abstract 4298: High-dose vitamin C induces ROS-dependent calreticulin exposure to drive immunogenic cell death and cancer immune surveillance

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Abstract Background: High-dose vitamin C (VitC) has shown superior anticancer activity in immunocompetent compared with immunodeficient mice, suggesting an immune-dependent mechanism of action. Because high-dose VitC generates substantial reactive oxygen species (ROS), we hypothesized that ROS might induce immunogenic cell death (ICD)—a regulated form of cell death characterized by the release of damage-associated molecular patterns (DAMPs) that enhance antigen presentation and promote antitumor immunity. Methods: Spatial transcriptomic and immunofluorescence analyses were performed on breast and colon tumors from mice treated with high-dose VitC to quantify oxidative stress, DAMP mobilization, and immune cell infiltration. To dissect the functional role of ROS and ICD, mice were treated with high-dose VitC in combination with the antioxidant N-acetylcysteine or an antibody blocking calreticulin (an early DAMP essential for ICD induction). Results: VitC treatment caused marked oxidative stress in tumors from both immunocompetent and immunocompromised mice; however, tumor growth inhibition occurred exclusively in immunocompetent animals. High-dose VitC triggered ROS-dependent exposure and release of the DAMPs calreticulin and HMGB1, respectively. This was accompanied by substantial remodeling of the tumor microenvironment, including increased infiltration of cytotoxic CD8+ T cells and natural killer cells, and a reduction in immunosuppressive regulatory T cells. Blocking calreticulin effectively disrupted the ICD cascade, prevented immune microenvironment remodeling, and completely abrogated the antitumor efficacy of VitC. Conclusions: High-dose VitC promotes ICD through ROS-dependent mobilization of calreticulin and HMGB1, and calreticulin is required for its immune-mediated antitumor activity. These results provide a mechanistic rationale for ongoing translational analyses within the ALFEO clinical trial (ECTR2022-502101-15-00), which is evaluating high-dose VitC in combination with nivolumab and ipilimumab in mismatch-repair-proficient colorectal cancer. Funded by the Italian Ministry of Health Next Generation EU - PNRR M6C2 - PNRR-MAD-2022-12376593. Citation Format: Alessandro Cavaliere, Federica Maione, Marco Macagno, Vito Amodio, Rosaria Chilà, Marcello Turi, Marc Escobosa, Giovanni Germano, Simona Lamba, Chiara Baretta, Anita Brignacca, Valeria Pessei, Elena Perez, Daniela Grases, Alice Bartolini, Fabio Penna, Eduard Porta, Manel Esteller, Dieter Saur, Roland Rad, Annamaria Gullà, Alberto Bardelli, Teresa Troiani, Salvatore Siena, Andrea Sartore-Bianchi, Federica Di Nicolantonio. High-dose vitamin C induces ROS-dependent calreticulin exposure to drive immunogenic cell death and cancer immune surveillance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4298.

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