Macrophage–tumor cell juxtacrine signaling activates a ferroptosis-protective circuit that drives radioresistance

While residual tumor cells are known to exploit local stromal cues for survival after RT, the cellular interactions within the irradiated tumor microenvironment that allow tumor cells to evade regulated cell death remain poorly defined. Here, we uncover a contact-dependent juxtacrine–paracrine signaling circuit between macrophages and tumor cells that suppresses ferroptotic cell death and facilitates regrowth after RT.

A kinome-wide siRNA screen in an irradiated co-culture model reveals Ephrin receptor B4 (EphB4) as a key regulator of macrophage-driven tumor survival. RT-induced EphB4 in tumor cells engages ephrinB2 on macrophages to trigger bidirectional signaling, which in turn activates ferroptosis-protective transcriptional programs in tumor cells and stimulates TLR2–NF-κB–dependent IL-6 production in macrophages. EphB4 also promotes tumor-intrinsic secretion of cathepsin S (CTSS), amplifying macrophage IL-6 release and establishing a feedforward loop that sustains a ferroptosis-refractory state.