A Tumor-Microenvironment-Activatable Molecular Pro-Theranostic Agent for Photodynamic and Immunotherapy of Cancer

Cancer-associated fibroblasts (CAFs) are the major components of the tumor-associated matrix and play an important role in tumor progression and immunosuppression. Therefore, precise theranostics of CAFs are beneficial for CAFs-targeted therapies. However, imaging agents enabling precise theranostics of CAFs have been rarely exploited. To tackle this issue, a molecular pro-theranostic probe (FMP) with activatable fluorescence, photoacoustic (PA) imaging, and photodynamic therapy (PDT) is developed in response to fibroblast activation protein a (FAPa) overexpressed in >90% types of CAFs and some tumor cells. Attributed to efficient activatable phototoxicity toward CAFs and tumor cells, together with activated immunogenic cell death (ICD), complete tumor regression of primary tumors and abscopal effect of distant tumors are observed in a 4T1-tumor-bearing mice model. By integration with PD-L1 checkpoint blockade immunotherapy, enhanced systemic immune responses are evoked to obtain long-lasting tumor suppression of both primary and distant tumors as well as arrest systemic cancer metastasis in living mice.

Automated summary

Cancer-associated fibroblasts (CAFs) are major components of the tumor-associated matrix and play a crucial role in tumor progression and immunosuppression. A new molecular pro-theranostic probe (FMP) with activatable fluorescence, photoacoustic imaging, and photodynamic therapy has been developed to specifically target CAFs. This probe shows efficient activatable phototoxicity towards CAFs and tumor cells, leading to complete regression of primary tumors and abscopal effects on distant tumors in a mouse model. Furthermore, when combined with PD-L1 checkpoint blockade immunotherapy, it also induces enhanced systemic immune responses and long-lasting tumor suppression in living mice.