IR reprograms the TME, initiating both pro-tumor and anti-tumor effects. Host immune status and other factors, such as microbiome populations, can affect tumor immunity. Left: Anti-tumor effects of IR. DCs are activated by RNA and DNA sensing pathways, which results in production of type I IFN, IFN-stimulated genes (ISGs), cytokines, and chemokines. DCs and inflammatory macrophage activate T cells to produce more IFN-γ, TNF-α, and granzyme B (GZMB), and kill tumor cells. Right: Pro-tumor effects of IR. IR induces PD-L1 and CTLA-4 expression in tumors. IR also induces infiltration of MDSCs, TAMs, and Tregs, which collectively inhibit T cell cytotoxic function and promote tumor growth. IR also induces overexpression of purinergic signaling to introduce radioresistance. Bottom: Outside of the tumor, products of certain bacteria strains activate or inhibit DC functions via TLRs. Fungus overgrowth or certain metabolites result in T cell exhaustion or radioresistance, respectively. MMP, matrix metalloproteinase; SCFA, short chain fatty acid. Figure created with BioRender.