Potentiating mild photothermal therapy via CDK12/13-mediated AKT suppression to orchestrate ferroptosis-apoptosis crosstalk for vaccine-like immunity.

BACKGROUND

Mild photothermal therapy (MPTT) offers a safe thermal window but typically fails to trigger sufficient immunogenic inflammation for durable tumor control. Reprogramming the "cold" tumor microenvironment into a pro-inflammatory state is essential for effective immunotherapy.

METHODS

We established a synchronized intervention strategy combining MPTT with CDK12/13 inhibition (SR4835) and TGF-β blockade (SB431542). We investigated the molecular crosstalk between ferroptosis and apoptosis and its impact on remodeling the tumor inflammatory landscape.

RESULTS

Mechanistically, MPTT intensified ROS-driven lipid peroxidation to potentiate ferroptosis, while SR4835 perturbed the CDK12/13-AKT axis to activate mitochondrial apoptosis. This synergy generated a robust pro-inflammatory immunogenic cell death (ICD) phenotype. Furthermore, TGF-β blockade dismantled immunosuppression, restoring the CD8⁺/Treg balance and fostering a pro-inflammatory cytokine milieu. Consequently, this regimen suppressed primary and distant tumors, reduced metastasis, and notably prevented tumor recurrence by activating memory T cells, thereby establishing durable vaccine-like immunity.

CONCLUSION

These findings demonstrate that orchestrating ferroptosis-apoptosis crosstalk effectively reprograms the immune microenvironment. By repositioning MPTT from a local thermal tool to a driver of antitumor inflammation, this study establishes a mechanism-based framework for treating immunologically cold solid tumors.