Photodynamic therapy synergizes with PD-L1 checkpoint blockade for immunotherapy of CRC by multifunctional nanoparticles

Checkpoint inhibitors, such as anti-PD-1/PD-L1 antibodies, have been shown to be extraordinarily effective, but their dura-ble response rate remains low, especially in colorectal cancer (CRC). Recent studies have shown that photodynamic therapy (PDT) could effectively enhance PD-L1 blockade therapeutic effects, although the reason is still unclear. Here, we report the use of multifunctional nanoparticles (NPs) loaded with photosensitized mTHPC (mTHPC@VeC/T-RGD NPs)-medi-ated PDT treatment to potentiate the anti-tumor efficacy of PD-L1 blockade for CRC treatment and investigate the under-lying mechanisms of PDT enhancing PD-L1 blockade thera-peutic effect in this combination therapy. In this study, the mTHPC@VeC/T-RGD NPs under the 660-nm near infrared (NIR) laser could kill tumor cells by inducing apoptosis and/ or necrosis and stimulating systemic immune response, which could be further promoted by the PD-L1 blockade to inhibit primary and distant tumor growth, as well as building long-term host immunological memory to prevent tumor recur-rence. Furthermore, we detected that mTHPC@VeC/T-RGD NP-mediated PDT sensitizes tumors to PD-L1 blockade ther-apy mainly because PDT-mediated hypoxia could induce the hypoxia-inducible factor 1a (HIF-1a) signaling pathway that upregulates PD-L1 expression in CRC. Taken together, our work demonstrates that mTHPC@VeC/T-RGD NP-mediated PDT is a promising strategy that may potentiate the response rate of anti-PD-L1 checkpoint blockade immunotherapies in CRC.

Automated summary

Recent studies show that photodynamic therapy (PDT) can enhance the therapeutic effects of PD-L1 blockade in colorectal cancer (CRC) by inducing tumor cell death, stimulating immune response, and preventing tumor recurrence through upregulation of PD-L1 expression via the hypoxia-inducible factor 1a (HIF-1a) signaling pathway. This combination therapy using multifunctional nanoparticles loaded with photosensitized mTHPC (mTHPC@VeC/T-RGD NPs) shows promise in improving the response rate of anti-PD-L1 checkpoint blockade immunotherapies in CRC.