Abstract With advent of carbon ion radiotherapy (CIRT) the spatio-temporal precision of external-beam radiotherapy has nearly reached the physical limits. We sought to investigate the potential of CIRT in reprograming the tumor immune microenvironment (TIME). To this end, three syngeneic tumor models were systematically investigated for their response to fractionated (5 x 3 Gy) CIRT vs. standard photon irradiation (XIRT). The models included the paradigmatic C57BL/6 tumor models of colorectal carcinoma (MC-38) and prostate cancer (RM1) as well as genetically engineered non-small cell lung cancer model (Pik3ca+, p53+/−, Y856). We observed substantially augmented antitumoral activity and relative biological effectiveness (RBE) of CIRT vs. XIRT in all three models. Intriguingly, CIRT achieved 100% cure rates in MC-38 and 67% in the Y856 model and increased the median overall survival (OS) three-fold vs. XIRT in the RM1 model. Immunohistological, single-cell transcriptome, and CyTOF analyses revealed enhanced immune cell infiltration in CIRT-treated tumors compared to controls. Moreover, enhanced infiltration of intravenously transferred Superparamagnetic Iron Oxide Nanoparticle (SPION) labelled T cells after CIRT was traced by MRI. The antitumoral responses elicited by CIRT could be significantly reduced in all three tumor models by abrogating the adaptive immune response via depletion of cytotoxic T cells using anti-CD8a antibodies. Additional experiments in immunocompromised athymic nude mice (Foxn1nu/nu) confirmed the significant impact of adaptive immunity in CIRT-elicited antitumoral effects with marked reduction of OS and zero cure rates across all three models. To examine the durability of CIRT-induced in-situ tumor vaccination, cured mice were rechallenged on abscopal sites at day 77 post-CIRT. In the MC-38 model, 100% of the abscopal tumors were rejected within 14 days after implantation indicating that CIRT induces a robust and durable systemic antitumor immunity. Together, our findings highlight the pivotal contribution of adaptive immunity to effective CIRT-induced TIME reprogramming for curative treatments. CIRT may provide novel and effective means of high-precision spatio-temporally controlled in-situ tumor vaccination. Citation Format: Sarah Meister, Matilde Recusani, Maximilian Knoll, Ralph Sinn, Aoife Gahlawat, Jennifer Furkel, Michael Breckwoldt, Dirk Jäger, Jürgen Debus, Amir Abdollahi. High-precision carbon ion radiotherapy elicits effective in-situ tumor vaccination and durable antitumor immunity 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 3512.
Meister et al. (Fri,) studied this question.