Selective antitumor activity of Tumor Treating Fields (TTFields) involving molecular factors in cancer cells and tumor microenvironment

Abstract

The local application of low-intensity electric fields at intermediate frequencies (Tumor Treating Fields - TTFields) has emerged as an effective anticancer treatment in conjunction with chemotherapy and immunotherapy for several solid tumors. Despite this progress, the phenotypic and genetic determinants underlying tumor sensitivity to TTFields remain largely unexplored, representing a critical gap in our understanding. This review provides a comprehensive analysis of preclinical and translational studies describing the cellular factors that influence the anticancer properties of TTFields. An overview of recent omics studies on the complex cellular and molecular processes initiated by TTFields has revealed important mechanisms of action that warrant further investigation for their therapeutic potential. The goal is to identify effects that can be leveraged to develop rational, synergistic co-treatments with anticancer agents that have complementary modes of action. In particular, the ability of TTFields to modulate the tumor microenvironment and reverse the local and systemic immunosuppression could represent a promising strategy to enhance the efficacy of immunotherapy across different tumor types.

Keywords: Anticancer therapy; Preclinical studies; Solid tumors; Tumor Treating Fields (TTFields); Tumor microenvironment.

Graphical abstract

Fig. 1

Physical and biological properties involved in the selectivity of TTFields against cancer cells. Frequency, intensity, and locoregional delivery, as well as cell proliferation rates, karyotypes and gene alterations have been examined for their role in mediating TTFields selectivity. However, few study were aimed at determining predictors of responsiveness to this treatment. Created with BioRender.com.

Fig. 2

Lack of correlation between cell doubling time at baseline and sensitivity to TTFields. A) Growth inhibition values after 72 h of exposure to TTFields, calculated as the percentage of control cells, were collected from different preclinical studies involving several cancer cell lines (Supplementary Table). All data are plotted versus cell doubling time, after grouping the cells based on the treatment intensity. No significant correlation between the two parameters is observed. B) After dividing the cells into two populations with different sensitivity to TTFields, doubling time distributions were compared. Doubling times are not statistically different in the two populations according to Student’s t-test p > 0.05.

Fig. 3

Karyotype and mutational status of certain genes in sensitive and less sensitive cell lines to TTFields treatment. Some studies have hypothesized that these genes may play a role in the response to TTFields (Table 1). Sensitive cell lines experience a growth inhibition greater than 50 % after 72 h of treatment with TTFields at an intensity of <1.2 V/cm RSM, while less sensitive cell lines experience a growth inhibition less than 50 % when treated with an intensity of 1.7 V/cm RSM. Karyotype and mutational status for each cell line were derived from the Cell Line Project of COSMIC database (https://cancer.sanger.ac.uk/cell_lines), unless specified otherwise. (*) Karyotype and mutational status derived from [24]. (**) Karyotype and mutational status derived from www.cellosaurus.org. (***) Karyotype and mutational status derived from [92].

Fig. 4

Main mechanisms of action of TTFields derived from omics studies that could be exploited to design co-treatment options. Some of these co-treatments have already been tested in preclinical or clinical studies, while others, such as those involving agents that affect cell differentiation and epithelial to mesenchymal transition (EMT), represent potential therapeutic strategies that are worthy of investigation. Created with BioRender.com.