Targeting of Focal Adhesion Kinase enhances the immunogenic cell death of PEGylated liposome doxorubicin to optimize therapeutic responses of immune checkpoint blockade

Abstract

Immune checkpoint blockade (ICB) is widely considered to exert long-term treatment benefits by activating antitumor immunity. However, many cancer patients show poor clinical responses to ICB due in part to the lack of immunogenic niche. Focal adhesion kinase (FAK) is frequently amplified and acts as an immune modulator across cancer types. However, evidence illustrates that targeting FAK is most effective in combination therapy rather than in monotherapy. Here, we demonstrated that the FAK inhibitor, IN10018, and pegylated liposome doxorubicin (PLD) exerted effective antitumor activity clinically. It is noteworthy that the regimen exhibited response latency and long-lasting effects, outcomes frequently observed in immunotherapy. Our preclinical study confirmed that the 2-drug combination can maximize the immunogenic cell death (ICD) of cancer cells. Thereby, this approach primed the tumor microenvironment, supplementing it with sufficient tumor-infiltrating lymphocytes (TILs) to activate antitumor immunity. The animal studies confirmed that the antitumor effects of ICB can be significantly enhanced by this doublet regimen. Finally, a further clinical trial exhibited that the triplet combination of PD-1 blockade, IN10018, and PLD has already established promising antitumor potency in the real world.