ArticleResearch square2026
Tumor Treating Fields (TTFields) sensitize anti-PD1-resistant lung tumors to PD1 blockade and remodel myeloid and lymphoid states.
Article in Research square, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Primary resistance to programmed cell death protein 1 (PD1) blockade is sustained by defective antigen presentation, immunosuppressive myeloid programs, regulatory T-cell (Treg) dominance, and dysfunctional lymphocyte states. Tumor Treating Fields (TTFields) are non-ionizing alternating electric fields with established antiproliferative activity; however, whether they can overcome resistance to immune checkpoint blockade remains unclear. Methods: The antitumor and immunomodulatory effects of TTFields were investigated in anti-PD1-resistant 344SQR murine lung adenocarcinoma cells and syngeneic tumors. Cells were exposed to TTFields for 24, 48, or 72 h and evaluated for proliferation, clonogenic survival, and transcriptional pathway changes. Tumor-bearing mice received control treatment, anti-PD1, matched heating control, TTFields, or their combinations. Tumor growth, survival, and pulmonary metastatic burden were assessed, and tumor-infiltrating immune populations were characterized by single-cell RNA sequencing and T-cell receptor clonotype analysis. Results: TTFields suppressed tumor-cell proliferation and clonogenic survival in a time-dependent manner, with maximal inhibition at 48 h and partial recovery at 72 h. This biphasic response coincided with early suppression followed by reactivation of cell-cycle, metabolic, and interferon-related transcriptional programs. Anti-PD1 monotherapy showed minimal activity in vivo, whereas TTFields combined with anti-PD1 delayed tumor growth, reduced pulmonary metastases, and prolonged survival. Single-cell analysis showed that TTFields decreased Treg abundance, increased the CD8 Conclusions: TTFields sensitized anti-PD1-refractory lung tumors to PD1 blockade and induced coordinated remodeling of tumor-cell fitness and the tumor immune microenvironment. These findings identify TTFields as a potential tumor-conditioning strategy for overcoming resistance to immune checkpoint blockade.
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