Radiotherapy, inflammation, and the myeloid perspective

Abstract Radiotherapy (RT) has long been regarded as a local treatment modality designed to eradicate tumor cells through targeted deoxyribonucleic acid (DNA) damage and, more recently, as an in situ vaccine capable of triggering the abscopal effect. However, increasing evidence now defines RT as a systemic immune modulatory intervention that elicits both antitumor and tumor growth-promoting effects. The recently described “badscopal effect”, the paradoxical progression or growth acceleration of non-irradiated disease associated with systemic immunosuppressive and growth-factor programs initiated by the irradiated lesion, highlights that RT may, under certain inflammatory and cellular contexts, foster immune tolerance or accelerate distant disease progression. Central to this duality is the host’s capacity to integrate and balance antitumor and pro-tumor responses following RT. Unlike the relatively binary activation states often attributed to T cells, myeloid cells exhibit high plasticity, integrating signals of DNA damage, hypoxia, and tissue repair to direct the inflammatory responses that inhibit or promote tumor growth. In this review, we examine how RT induces dual inflammatory programs, as a partial explanation as to why classical abscopal models incompletely capture clinical practice and how myeloid plasticity emerges as a central determinant of systemic responses to RT, with important implications for the rational design of combination therapies.