Year: 2026
Type: preprint
Abstract: Residual disease remains a major obstacle for achieving durable responses in patients treated with oncogene-targeted therapy. Drug-tolerant persister (DTP) cells emerging under treatment and persisting in residual tumors are considered to be the root of acquired resistance, yet their contribution to immune evasion in on-treatment tumors is poorly defined. Here, we show in the context of EGFR-mutant lung cancer that DTP cells actively contribute to the formation of an immunosuppressive tumor microenvironment during EGFR tyrosine kinase inhibitor (TKI) therapy. In syngeneic mouse models and in patients, EGFR TKI therapy leads to an accumulation of immunosuppressive macrophages, which is strictly treatment-dependent and fully reversible upon treatment cessation or progressive disease, respectively. Quiescent DTP cells directly drive the recruitment and immunosuppressive reprogramming of monocytes and macrophages through a YAP-driven secretome, and the DTP-reprogrammed monocytes suppress T cell proliferation and effector functions in vitro . Co-targeting YAP with a TEAD inhibitor ORM-47286 rewires the DTP secretome and inhibits macrophage reprogramming in vitro , and prevents immunosuppressive macrophage accumulation and improves the efficacy of EGFR TKI therapy in immunocompetent mouse models. Our findings highlight the previously unappreciated role of DTP cells in modulating the tumor microenvironment in on-treatment tumors, and position the treatment-induced YAP/TEAD activity in DTP cells as an important driver of adaptive immunosuppression during EGFR-targeted therapy.
Authors: Meija Honkanen, Jonas Baumgarten, Nikol Dibus, Jenna H. Rannikko, Milos Gojkovic, Paloma Cejas, Yingtian Xie, Zsuzsanna Ortutay, Johannes Merilahti, Mari Tienhaara, Iman Farahani, Steffen Boettcher, Pasi A. Jänne, Otto Kauko, Raphael A. Nemenoff, Lynn E. Heasley, Heidi M. Haikala, Maija Hollmén, Kari J. Kurppa
Institutions: University of Turku, University of Helsinki, Institute for Molecular Medicine Finland, HiLIFE – Elämäntieteiden Instituutti, Harvard University, Dana-Farber Cancer Institute, Åbo Akademi University, University of Zurich, University Hospital Zurich, University of Colorado Anschutz, VA Eastern Colorado Health Care System, Tampere University, University of Tampere
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7125591123