The link between intracellular calcium signaling and exosomal PD-L1 in cancer progression and immunotherapy

Exosomes are small membrane vesicles containing microRNA,RNA,DNA fragments,and proteins that are transferred from donor cells to recipient cells.Tumor cells release exo-somes to reprogram the factors associated with the tumor microenvironment(TME)causing tu-mor metastasis and immune escape.Emerging evidence revealed that cancer cell-derived exosomes carry immune inhibitory molecule program death ligand 1(PD-L1)that binds with re-ceptor program death protein 1(PD-1)and promote tumor progression by escaping immune response.Currently,some FDA-approved monoclonal antibodies are clinicallyused for cancer treatment by blocking PD-1/PD-L1 interaction.Despite notable treatment outcomes,some pa-tients show poor drug response.Exosomal PD-L1 plays a vital role in lowering the treatment response,showing resistance to PD-1/PD-L1 blockage therapy through recapitulating the ef-fect of cell surface PD-L1.To enhance therapeutic response,inhibition of exosomal PD-L1 is required.Calcium signaling is the central regulator of tumorigenesis and can regulate exosome biogenesis and secretion by modulating Rab GTPase family and membrane fusion factors.Im-mune checkpoints are also connected with calcium signaling and calcium channel blockers like amlodipine,nifedipine,lercanidipine,diltiazem,and verapamil were also reported to suppress cellular PD-L1 expression.Therefore,to enhance the PD-1/PD-L1 blockage therapy response,the reduction of exosomal PD-L1 secretion from cancer cells is in our therapeutic consider-ation.In this review,we proposed a therapeutic strategy by targeting calcium signaling to inhibit the expression of PD-L1-containing exosome levels that could reduce the anti-PD-1/PD-L1 therapy resistance and increase the patient's drug response rate.