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All living matter is under constant environmental stress that jeopardizes the genomic integrity of individual cells and the functional integrity of tissues in higher organisms. At the level of non-post-mitotic tissues, stem cells constantly divide to give rise to all lineages of differentiated cells. Once thought to be unidirectional, cellular differentiation can now be reversed and overexpression of developmental transcription factors can turn somatic cells into induced pluripotent stem cells by means of reprogramming. This process is critically dependent on optimal co-stimulation of the innate immune response through activation of pattern recognition receptors (PRRs) by pathogen and/or damage associated molecular patterns (PAMPs/DAMPs). Ionizing radiation (IR) being an extreme form of genotoxic stress, can lead to the release of DAMPs. Our lab has identified that radiation induces the formation of cancer stem cells from non-cancer stem cells, a process termed IR-induced phenotype conversion. Cellular plasticity, an umbrella term encompassing reprogramming and radiation-induced phenotypic conversion events, allows cells to effectively respond to triggers that would otherwise compromise them. The underlying mechanisms driving these processes are incompletely understood but PAMPs and DAMPs are readily involved and employ common pathways downstream of their respective receptors. Glioblastoma (GBM) is a highly aggressive, malignant primary brain tumor for which cancer stem cells play a critical role in therapy resistance, recurrence and overall disease progression. This in combination with the radiation-induced cellular plasticity response could further exacerbate patient outcome if unaccounted for. Thus, to better understand the underlying mechanisms driving IR-induced cellular plasticity events, cancer stem cell maintenance/self-renewal (SFAs, ELDAs) and de novo stem cell induction (reprogramming assays) were studied using patient-derived glioblastoma cells. Several Toll-like receptors (TLRs) as well as components of the free cytosolic DNA sensing machinery, the cGAS/STING pathway, were evaluated. Our main study findings were as follows: 1) stem cell maintenance following irradiation is mediated through cGAS-independent STING signaling, with potential crosstalk with TLR4 and TLR9 and 2) de novo stem cell induction following irradiation implicates TLR3 signaling and potentially other receptors and processes affected by chloroquine. Collectively, these point to a direct link between innate immune signaling and IR-induced cellular plasticity events.