Coupling oxidative de-stabilization with immune activation overcomes radioresistance in hepatocellular carcinoma

Radioresistance in hepatocellular carcinoma (HCC) is a coordinated adaptive state rather than failure of a single pathway, sustained by reinforced redox buffering and suppressed immune activation. Strategies that intensify radiation damage without disrupting this state have shown limited efficacy. We sought to determine whether radiosensitization can be achieved by destabilizing tumor oxidative homeostasis while restoring immune competence.

A BSA-templated Fe/Mn nanoassembly incorporating the thiol-reactive agent RRX-001 and folate targeting (BFMR-FA) was developed as a multifunctional and MRI-visible platform. Its biological effects were evaluated across radioresistant cellular systems, organoids, and orthotopic tumor models.

BFMR-FA shifts the redox equilibrium of tumor cells beyond a recoverable threshold. By depleting glutathione and suppressing the SLC7A11-GPX4 axis, it converts radiation-induced oxidative stress from a transient signal into sustained lipid peroxidation, resulting in convergent ferroptotic and apoptotic cell death. This transition is accompanied by the emergence of immunogenic stress signals and activation of the STING-TBK1-IRF3 pathway, enabling dendritic cell maturation and expansion of cytotoxic T-cell responses. In vivo, these effects translate into near-complete suppression of radioresistant tumor growth with systemic tolerance. The Fe/Mn composition enables direct visualization of intratumoral delivery by T1-weighted MRI.

These findings support a model in which radiosensitization is achieved not by amplifying tumor damage alone, but by collapsing the adaptive redox state that constrains it. The resulting oxidative destabilization coupled with immune activation defines an oxidative homeostasis collapse-driven radio-immuno synergy, providing a generalizable framework for overcoming therapeutic resistance in solid tumors.