Visible light reprograms MSCs and T cells into tumor-suppressive states via OPN4-mediated epigenetic remodeling.

Cellular metabolism critically influences tumor resistance. Biophysical stimulations such as mechanical vibration and electrical pulses can reprogram mesenchymal stem cells (MSCs) and T cells into tumor-suppressive states. Here, we investigated whether optical pulses (OP) could similarly promote an anti-tumor microenvironment. Using mechanical and electrical stimulation as controls, we examined optically stimulated MSCs and T cells and their conditioned medium (CM) in breast cancer and osteoclast models. OP elicited color-specific effects: blue light induced direct tumor cell death, whereas green and red light converted MSCs into induced tumor-suppressing (iTS) cells. This conversion was mediated by OPN4, independent of the Piezo1 pathway engaged by mechanical and electrical cues. Green/red pulses enhanced nucleosome scattering, increased the NAD⁺/NADH ratio, reduced the repressive histone mark H3K9me3, and activated demethylases KDM3A/KDM4. Proteomic profiling revealed enrichment of transferrin receptor (TFRC) and Annexin A2 (ANXA2) in CM, which may suppress tumors via CD44 interaction and are associated with reduced immune-evasive signaling, including Programmed Death-Ligand 1 (PD-L1). These findings demonstrate that visible light pulses can epigenetically reprogram MSCs and T cells, offering a potential therapeutic strategy for breast cancer and bone metastasis.