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Background Glioblastoma (GBM)’s immunosuppressive tumor microenvironment (TME) excludes T cells, thwarting current immunotherapies. To overcome this barrier, we reprogramed GBM cells into induced antigen-presenting cells (iAPC) using a computationally guided gene-therapy, which unexpectedly sharply upregulated pyroptotic inflammasome components. We hypothesize that combining iAPC conversion with DNA-damaging therapies [temozolomide (TMZ) or Tumor-Treating Fields (TTFields)] will trigger localized pyroptotic immunogenic cell death (ICD), unleashing tumor antigens and danger signals in situ. This turns the tumor into its own vaccine depot, ‘heating up’ the cold TME and mobilizing a localized, T cell-mediated anti-tumor response.Methods mPIIB ( Pu.1/Irf8/Id2/Batf3) and hPI (PU.1/IKZF1) cell-fate determinant cocktails were delivered via lentiviral transduction into a panel of murine and human GBM cell lines and patient-derived glioma stem cells (GSC), respectively. Upregulation of key pyroptotic inflammasome components (e.g., GSDMA/D/E, AIM2, PYCARD, Caspases-1/3/4/8, TLR3/4, NLRP3, and IL-1β/18) was confirmed by bulk and single-cell RNA-sequencing. Reprogrammed iAPCs and GFP-transduced controls were then treated with temozolomide (100µM, 72h) or TTFields (200kHz, 1.5V/cm, 72h), and pyroptosis was quantified by morphological changes, cleaved Caspase-1 p10 production, and live-cell imaging coupled with a LDH release assay. In immunocompetent mouse models bearing orthotopic, syngeneic GBM transduced with mPIIB or an empty virus, animals were randomized to receive TMZ or the vehicle. Survival was the primary endpoint, with tumor volume (bioluminescence) and immune TME profiling (IHC and cytometry) as secondary endpoints.Results GBM reprogramming triggered marked upregulation of pyroptosis genes, reaching or exceeding levels in natural APC controls –– e.g., AIM2 (3.8-fold), Caspase-1 (4.4-fold), GSDMD (same) versus controls. Upon TMZ or TTFields treatment, iAPCs displayed classic pyroptotic morphology alongside a 2.5–6-fold increase in Caspase-1 activity (p=0.0292) and a 6.5–20-fold rise in pyroptotic cell death (p=0.0031), demonstrating synergy between DNA damage and inflammasome activation. In vivo, mPIIB+TMZ significantly reduced tumor growth and extended survival over mPIIB alone (HR 0.34; p=0.0058) and TMZ alone (HR 0.29; p=0.0126), although 30% of mice succumbed to treatment-related CNS swelling. Treated tumors shifted from nearly T-cell-free to heavily infiltrated, with >40-fold increases in CD4+ and >100-fold increases in activated (CD25+/GZMB+) CD8+ T cells compared to controls.Conclusions Reprogramming GBM cells into iAPCs unleashes pyroptosis that, when combined with DNA-damaging therapy, converts tumors into in situ vaccines and extends survival. Treatment-related neuroinflammation underscores the need for targeted immunomodulation; accordingly, we are developing a next-generation gene therapy co-expressing iAPC factors with soluble PD-1 and VEGFR decoys to sustain anti-tumor T cells while limiting cerebral edema.