Astatine-211 injury induces an immunostimulatory melanoma-cell state and promotes systemic antitumor immunity
- 1The University of Osaka
Abstract
Targeted alpha therapy is generally evaluated by absorbed dose and direct tumor-cell killing, but whether alpha-particle-injured tumor cells can induce systemic antitumor immunity remains poorly defined. We investigated the immunogenic consequences of astatine-211 (211At) injury in a prophylactic melanoma vaccination-challenge model. B16F10 cells were exposed ex vivo to 211At, etoposide, or ultraviolet irradiation under conditions that reduced viable-cell counts at 24 hours to approximately 40% of untreated controls. Injured cells were administered subcutaneously to syngeneic C57BL/6J mice before intravenous challenge with viable B16F10 cells. Vaccination with cells exposed to 1 MBq/mL 211At suppressed pulmonary metastasis, reduced regulatory T-cell proportions, and elicited tumor-reactive interferon-{gamma} responses and antibodies. Transcriptomic profiling revealed enrichment of type I interferon, inflammatory, and chemokine-related signatures, together with suppression of cell-cycle, translation, and metabolic programs. At the cellular level, 211At injury was accompanied by {gamma}H2AX accumulation, G2/M arrest, increased reactive oxygen species and cytosolic double-stranded DNA, and senescence-like changes. These features arose without consistent increases in classical damage-associated molecular patterns or prominent induction of senescence-associated secretory phenotype factors at 1 MBq/mL. In vivo pharmacologic inhibition of stimulator of interferon genes (STING) signaling attenuated the antimetastatic effect of vaccination. Together, these findings demonstrate that 211At injury can generate an immunostimulatory tumor-cell state characterized by DNA damage and altered inflammatory signaling. STING contributes to the resulting immune protection, highlighting immunogenic tumor-cell conversion as a consideration in the design of targeted alpha therapies.
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BibTeX
@misc{mayusumi2026astatine211,
title = {{Astatine-211 injury induces an immunostimulatory melanoma-cell state and promotes systemic antitumor immunity}},
author = {K. Mayusumi and S. Magara and X. Huang and K. Kaneda-Nakashima and K. Ooe and M. Murakami and A. Toyoshima and H. Haba and X. Yin and K. Fukase and A. Shimoyama and K. Kabayama},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.22.760895},
url = {https://www.biorxiv.org/content/10.64898/2026.10.22.760895v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Astatine-211 injury induces an immunostimulatory melanoma-cell state and promotes systemic antitumor immunity
AU - K. Mayusumi
AU - S. Magara
AU - X. Huang
AU - K. Kaneda-Nakashima
AU - K. Ooe
AU - M. Murakami
AU - A. Toyoshima
AU - H. Haba
AU - X. Yin
AU - K. Fukase
AU - A. Shimoyama
AU - K. Kabayama
PY - 2026
DA - 2026/10/22
PB - bioRxiv
DO - 10.64898/2026.10.22.760895
UR - https://www.biorxiv.org/content/10.64898/2026.10.22.760895v1
AB - Targeted alpha therapy is generally evaluated by absorbed dose and direct tumor-cell killing, but whether alpha-particle-injured tumor cells can induce systemic antitumor immunity remains poorly defined. We investigated the immunogenic consequences of astatine-211 (211At) injury in a prophylactic melanoma vaccination-challenge model. B16F10 cells were exposed ex vivo to 211At, etoposide, or ultraviolet irradiation under conditions that reduced viable-cell counts at 24 hours to approximately 40% of untreated controls. Injured cells were administered subcutaneously to syngeneic C57BL/6J mice before intravenous challenge with viable B16F10 cells. Vaccination with cells exposed to 1 MBq/mL 211At suppressed pulmonary metastasis, reduced regulatory T-cell proportions, and elicited tumor-reactive interferon-{gamma} responses and antibodies. Transcriptomic profiling revealed enrichment of type I interferon, inflammatory, and chemokine-related signatures, together with suppression of cell-cycle, translation, and metabolic programs. At the cellular level, 211At injury was accompanied by {gamma}H2AX accumulation, G2/M arrest, increased reactive oxygen species and cytosolic double-stranded DNA, and senescence-like changes. These features arose without consistent increases in classical damage-associated molecular patterns or prominent induction of senescence-associated secretory phenotype factors at 1 MBq/mL. In vivo pharmacologic inhibition of stimulator of interferon genes (STING) signaling attenuated the antimetastatic effect of vaccination. Together, these findings demonstrate that 211At injury can generate an immunostimulatory tumor-cell state characterized by DNA damage and altered inflammatory signaling. STING contributes to the resulting immune protection, highlighting immunogenic tumor-cell conversion as a consideration in the design of targeted alpha therapies.
ER -