Time Rules the Efficacy of Immune Checkpoint Inhibitors in Photodynamic Therapy

Lack of adequate effector T cells infiltrated in tumor is one of the main problems in the failure of immune checkpoint blockade therapy (ICBT). Photodynamic therapy (PDT) induced acute inflammation can sensitize tumors and activate T cells, thus assisting immune checkpoint inhibitors (ICI) against tumor growth and metastasis. T cells maturation and activation lag 3 to 7 days behind PDT. However, such timing in the combination therapy of ICI and PDT is commonly ignored in designing numerous multi‐functional integrated nanomedicines. Herein, the authors illustrate that intervention timing of ICI after PDT affects the anti‐tumor efficacy. A tumor‐targeting nanomedicine is prepared by encapsulating indocyanine green into CD44 specifically binding material, a hyaluronic acid conjugated lipid poly(ethylene glycol). The PDT nanomedicine is designed to induce a robust immune response in tumor. The optimal group (Combo‐STAR), ICI gave 5 days after PDT, significantly suppresses local tumor growth and eliminates metastasis. What should be highlighted is the time point of administration because if ICI is given too early, T cells are immature, otherwise, T cells are exhausted if ICI is given too late. This work presents theoretical guidance for raising awareness of intervention timing when augmenting ICBT with immune response inducers in clinic.