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Tumor Electric Field Therapy (TEFT) disrupts mitosis in glioblastoma (GBM), but responses vary markedly among patients. In a retrospective cohort of TEFT-treated GBM, EGFR variant III (EGFRvIII) alteration is associated with shorter progression-free survival, prompting us to investigate a genotype-linked resistance mechanism. TEFT triggers a broadly shared bioenergetic stress response marked by activation of the AMPK-PPARα-CPT1A axis, whereas EGFRvIII primes IDO1 transcription through NF-κB. CPT1A further stabilizes IDO1 by promoting succinylation at lysine 377 through non-canonical LSTase-related activity, thereby limiting TRIM21-dependent ubiquitination and proteasomal degradation. Accumulated IDO1 increases kynurenine production and activates AhR, which upregulates DCLK1 and ARHGEF2 to preserve spindle organization and microtubule dynamics during electric-field exposure. Thus, EGFRvIII converts a general stress-adaptation pathway into a selective cytoprotective program. Genetic or pharmacological disruption of this pathway restores TEFT sensitivity in established and patient-derived GBM cells, organoids, and orthotopic models. Osimertinib suppresses the EGFRvIII-NF-κB-IDO1 arm and enhances TEFT efficacy, while exploratory clinical cases provide preliminary mechanism-informed support for the combination in recurrent EGFR-driven GBM. These findings define a genotype-field convergence mechanism linking metabolic adaptation to mitotic protection and support prospective evaluation of osimertinib plus TEFT.