Radionuclide-Stimulated Dynamic Therapy Induces Complementary Immunogenic Necroptosis and Apoptosis Cancer Cell Death Pathways

Authors

Christopher Egbulefu
Kvar Black
Xinming Su
Partha Karmakar
LeMoyne Habimana-Griffin
Gail Sudlow
Julie Prior
Ezugo Onejeme
Alex Zheleznyak
Baogang Xu
Yalin Xu
Alison Esser
Matthew Mixdorf
Evan Moss
Brad Manion
Cody Hongsermeier
Nisha Gamadia
Nicole Blasi
Luke Stallings
Chidube Alagbaoso
Nathan Reed
Matthew M Gubin
Chieh-Yu Lin
Robert Schreiber
Katherine Weilbaecher
Samuel Achilefu

Language

English

Publication Date

1-19-2026

Journal

Communications Biology

DOI

10.1038/s42003-026-09555-5

PMCID

41554980

PubMedCentral® Posted Date

1-19-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Radionuclide-stimulated dynamic therapy (RaST) utilizes Cerenkov-radiating radiopharmaceuticals to activate light-sensitive drugs and materials, generating reactive oxygen species (ROS) that inhibit cancer progression. However, the underlying cell death mechanisms are not fully understood. Using ROS-regenerative nanophotosensitizers coated with a tumor-targeting transferrin-titanocene complex and radiolabeled 2-fluorodeoxyglucose, we found that RaST induced apoptosis and necroptosis, characterized by the activation of RIPK-1, RIPK-3, nuclear factor kappa B, and mixed lineage kinase domain-like pseudokinase, leading to membrane permeabilization, cytokine release, and the expression of immunogenic damage-associated molecular patterns. In immune-deficient breast tumor-bearing mice with adequate stroma and growth factors, RaST did not prevent tumor growth or lung metastasis. However, in immunocompetent models, RaST induced a partial and complete response (CR) with no metastasis, driven by the recruitment of CD11b+, CD11c+, and CD8b+ effector immune cells. A cancer-imaging agent, LS301, identified latent minimal residual disseminated tumors in the lymph nodes of the CR group. Although cancer cells in CR mice enhanced protumor cytokines and immune checkpoints over time, RaST maintained cancer control through dynamic redistribution of ROS-regenerative titanium dioxide nanoparticles from bones to spleen and lymph nodes, supporting sustained immunity. This study highlights how RaST reprograms tumor immunity, overcoming apoptosis resistance by activating complementary necroptosis.

Keywords

Animals, Necroptosis, Mice, Apoptosis, Female, Cell Line, Tumor, Humans, Reactive Oxygen Species, Radiopharmaceuticals, Immunogenic Cell Death, Breast Neoplasms, Breast cancer

Published Open-Access

yes

Recommended Citation

Egbulefu, Christopher; Black, Kvar; Su, Xinming; et al., "Radionuclide-Stimulated Dynamic Therapy Induces Complementary Immunogenic Necroptosis and Apoptosis Cancer Cell Death Pathways" (2026). Faculty, Staff and Student Publications. 5790.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5790