TYRO3 induces anti-PD-1/PD-L1 therapy resistance by limiting innate immunity and tumoral ferroptosis

Immune checkpoint blockade therapy has demonstrated promising clinical outcomes for multiple cancer types. However, the emergence of resistance as well as inadequate biomarkers for patient stratification have largely limited the clinical benefits. Here, we showed that tumors with high TYRO3 expression exhibited anti?programmed cell death protein 1/programmed death ligand 1 (anti?PD-1/PD-L1) resistance in a syngeneic mouse model and in patients who received anti?PD-1/PD-L1 therapy. Mechanistically, TYRO3 inhibited tumor cell ferroptosis triggered by anti?PD-1/PD-L1 and facilitated the development of a protumor microenvironment by reducing the M1/M2 macrophage ratio, resulting in resistance to anti?PD-1/PD-L1 therapy. Inhibition of TYRO3 promoted tumor ferroptosis and sensitized resistant tumors to anti?PD-1 therapy. Collectively, our findings suggest that TYRO3 could serve as a predictive biomarker for patient selection and a promising therapeutic target to overcome anti?PD-1/PD-L1 resistance.

Automated summary

Research shows that tumors with high TYRO3 expression exhibit resistance to PD-1/PD-L1 therapy by inhibiting tumor cell ferroptosis and altering the tumor microenvironment. Inhibition of TYRO3 promotes tumor ferroptosis and sensitizes resistant tumors to PD-1 therapy. This suggests that TYRO3 could be a predictive biomarker for patient selection and a promising therapeutic target to overcome resistance to PD-1/PD-L1 therapy.