Abstract While there is clear clinical evidence to support the therapeutic efficacy of low dose alternating electric fields (TTFields) in treating glioblastoma, their intracellular targets and mechanism of action remains poorly defined. Historically, TTFields have been thought to operate by inducing extensive plasma membrane blebbing during the entry into anaphase resulting in aberrant mitotic exit and cell death. However, we have found that cells exposed to TTFields exhibited increased granularity and evidence of endoplasmic reticulum stress and genotoxic stress suggesting other mechanisms to explain their clinical efficacy. Cells exposed to TTFields exhibited reductions in levels of culture media acidification and analysis of intracellular metabolism showed evidence for an increase in mitochondrial respiration and glutaminolysis pathway. Our previous analysis of data from the pivotal phase III EF-11 clinical trial showed that increased corticosteroid use was strongly correlated with poor outcomes in TTFields-treated patients, possibly by suppressing immune effector function required for to drive tumor regression. TTFields drives the cell surface expression of immune stimulatory stress marker proteins calreticulin, and the secretion of the Alarmin/DAMP protein, HMGB1 which are together suggest that TTFields can stimulate immunogenic cell death. Co-culture of bone marrow derived macrophages with TTFields-treated CT26 cells resulted in the up-regulation of cell surface activation markers in the macrophage population that was blocked by a monoclonal antibody directed against HMGB1. Further, supernatants from these co-cultures contained increased levels of pro-inflammatory cytokines and chemokines and a reduction of anti-inflammatory cytokines associated with the presence of the TTFields-treated cells relative to co-cultures containing naïve tumor cells. Further, in vivo, engrafted Lewis lung carcinoma tumors exhibited increased levels of granzyme positive cells following TTFields treatment. Together, these data suggest that TTFields affect cancer cells during interphase and this insult leads to alterations in cancer cell metabolism and increased tumor cell immunogenicity and thus act to drive increased immune recognition and tumor rejection. In patients, these effects are likely to be opposed by the immune suppressive functions within the tumor microenvironment and corticosteroid use. Therefore, this model of TTFields action may provide a therapeutically rational base to devise improved TTFields treatment strategies from. Citation Format: Eric T. Wong, Joshua Timmons, Kenneth D. Swanson. Tumor treating fields exert cellular and immunologic effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1707.