Mobilizing phospholipids on tumor plasma membrane implicates phosphatidylserine externalization blockade for cancer immunotherapy.

In "healthy" tumor cells, phosphatidylserine (PS) is predominately localized in the inner plasma membrane leaflet. During apoptosis, PS relocates to the outer leaflet. Herein, we established PS^out tumor models with tumor cells lacking PS flippase component CDC50A, constantly exposing PS but alive. PS^out tumors developed bigger than wild-type (WT) tumors, featuring M2 polarized tumor-associated macrophages (TAMs) and fewer tumor-antigen-specific T cells. The PS receptor TIM-3 is responsible for PS recognition. Employing an opposite tumor model, PSⁱⁿ, with tumor cells lacking the PS scramblase Xkr8 and unable to expose PS during otherwise normal apoptosis, we find that the accumulated apoptotic tumor cells produce and release cyclic GAMP (cGAMP) to immune cells to activate the STING pathway, leading to TAM M1 polarization, suppressed interleukin (IL)-10 secretion, and natural killer (NK) cell cytotoxicity. Silencing Xkr8 in vivo by either short hairpin RNA (shRNA) or small interfering RNA (siRNA) to achieve a PS externalization blockade provides robust therapeutic anti-tumor efficiency. [Display omitted] • PS^out tumors grow larger than WT, with an immune-suppressive tumor microenvironment • TIM-3 is responsible for PS sensing in PS^out tumors • PSⁱⁿ tumors activate STING, leading to TAM M1 polarization and NK cell cytotoxicity • Silencing Xkr8 in vivo to block PS externalization provides anti-tumor effects in mice Wang et al. show that externalized phosphatidylserine (PS) on cancer cells induces an immune-suppressive microenvironment to promote tumor growth, which is dependent on the PS receptor TIM-3. Blocking PS externalization by silencing the PS scramblase Xkr8 enhances anti-tumor immunity, suggesting Xkr8 as a potential therapeutic target. [ABSTRACT FROM AUTHOR]