Photobiomodulation mitigates the inhibitory effects of pirfenidone on cancer-associated fibroblasts and their pro-tumorigenic properties: a cause for concern.

Cancer-associated fibroblasts (CAFs) within the tumor microenvironment highly contribute to cancer progression and poor prognosis. Recent findings introduce pirfenidone, a medication for pulmonary fibrosis, as a promising repurposed candidate for inhibiting CAFs. Moreover, photobiomodulation (PBM), or low-level laser therapy, has surfaced as a potential modality against cancer; however, its impact on CAFs is not thoroughly comprehended. The present study scrutinized the effects of PBM, pirfenidone, and PBM+pirfenidone on CAFs, and their consequent impact on cancer cells using the CAF-conditioned media. After treating CAFs with PBM at wavelengths 660 and 980 nm with/without PFD and then culturing cancer cells in the prepared conditioned media, cell viability, gene expression, migration, and clonogenic potential were evaluated. Results indicated that PBM reduced the anti-fibrogenic effects of pirfenidone on CAFs and increased their viability. PBM compensated for inhibited migration-inducing effects of CAFs by pirfenidone on cancer cells and promoted their clonogenic potential. Gene expression studies uncovered modulation of EMT and stemness-related genes by PBM and pirfenidone. In conclusion, findings propose that PBM could maintain pro-tumorigenic effects of CAFs even following treatment with the anti-fibrotic agent pirfenidone; therefore, PBM should cautiously be used against cancer before further investigations expound the underlying mechanisms and optimize treatment protocols.