Photodynamic therapy remodels the prostate cancer microenvironment by suppressing cancer-associated fibroblast-mediated calcium signaling.

BACKGROUND

Prostate cancer (PCa) remains a leading cause of cancer burden in men worldwide. Photodynamic therapy (PDT) offers a minimally invasive therapeutic option, but the molecular mechanisms underlying its anti-tumor efficacy, particularly in the context of the tumor microenvironment, are not fully elucidated.

METHODS

Integrated bioinformatics analyses of bulk and single-cell transcriptomic datasets identified key PDT-responsive molecular pathways and cell populations in PCa. Functional enrichment and intercellular communication analyses were performed to investigate tumor-stroma cell interactions. The efficacy and mechanism of PDT were further validated using in vitro co-culture systems and in vivo xenograft models, with a focus on calcium signaling, CAF activation, and RGS2 regulation.

RESULTS

Transcriptomic analyses revealed significant enrichment of cancer-associated fibroblast (CAF)-related processes both in PCa progression and following PDT. CAFs promoted early epithelial malignancy via IGF1-IGF1R signaling, which was coupled to increased calcium influx in tumor cells. PDT disrupted this pro-tumorigenic axis, leading to suppressed CAF activation, reduced tumor cell viability, and a marked reduction of intracellular calcium levels. Eleven candidate PDT-responsive genes were identified, with RGS2 prioritized as a key protective factor modulating calcium signaling and tumor-stroma interactions. PDT upregulated RGS2 in both tumor and stromal compartments while downregulating calcium channel proteins.

CONCLUSION

PDT enhances therapeutic efficacy in PCa not only through direct tumor cell cytotoxicity, but also via reprogramming of the tumor microenvironment, primarily by disrupting the CAF-mediated IGF1/IGF1R‑calcium signaling axis and upregulating RGS2. Targeting this pathway may hold promise for developing more effective, personalized PDT-based therapeutic strategies in PCa.