Fibroblasts are a key component of the tumor microenvironment (TME) that can serve as a scaffold for
tumor cell migration and augment the
tumor's ability to withstand harsh conditions. When activated by external or endogenous stimuli, normal fibroblasts become cancer associated fibroblasts (CAFs), a heterogeneous group of stromal cells in the
tumor that are phenotypically and epigenetically different from normal fibroblasts. Dynamic crosstalk between
cancer cells, immune cells, and CAFs through
chemokines and surface signaling makes the TME conducive to
tumor growth. When activated, CAFs promote
tumorigenesis and
metastasis through several phenomena including regulation of
tumor immunity, metabolic reprogramming of the TME, extracellular matrix remodeling and contraction, and induction of therapeutic resistance. Ionizing radiation (radiation theraphy [RT]) is a potent immunological stimulant that has been shown to increase cytotoxic Teff infiltration and IFN-I stimulated genes. RT, however, is unable to overcome the infiltration and activation of immunosuppressive cells which can contribute to
tumor progression. Another paradox of RT is that, while very effective at killing
cancer cells, it can contribute to the formation of CAFs. This review examines how the interplay between CAFs and immune cells during RT contributes to organ
fibrosis, immunosuppression, and
tumor growth. We focus on targeting mechanistic pathways of CAF formation as a potentially effective strategy not only for preventing organ
fibrosis, but also in hampering
tumor progression in response to RT.