Multimodal immunopharmacologic screens identify drugs rewiring the cancer-immune interface
Natural killer (NK) cell-based therapies are a promising approach in cancer, but their efficacy is limited by impaired effector function and tumor-intrinsic resistance. To systematically identify therapeutic strategies that target both sides of the cancer-immune interface, we designed a multimodal immunopharmacologic screening platform comprising high-throughput co-culture drug screens, cytokine secretome profiling, single-cell perturbation screens, and genome-scale CRISPR screening, followed by validation in biobanked patient-derived models. Applying the platform across five blood cancer types, we identified protein kinase C (PKC) activation to simultaneously increase effector cytotoxicity and cytokine secretion through transcriptomic rewiring, and tumor susceptibility to NK cell killing through tumor-intrinsic PKC-δ. In patient samples, PKC activation sensitized NK-resistant leukemic progenitors to NK cell killing. In addition, NEDD8 inhibition enhanced NK function and shifted tumor TNF signaling towards pro-apoptotic pathways. Our platform provides a systematic approach to identify drugs rewiring both sides of the cancer-immune interface to circumvent tumor immune resistance.
Authors
- Hanna Duàn (ORCID: https://orcid.org/0000-0001-8318-130X)
- Emmi Järvelä (ORCID: https://orcid.org/0000-0002-5249-2508)
- Tero A. Aittokallio (ORCID: https://orcid.org/0000-0002-0886-9769)
- Emmi Jokinen (ORCID: https://orcid.org/0000-0002-0060-6868)
- Tiina Hannunen
- Olli Dufva (ORCID: https://orcid.org/0000-0002-8084-0282)
- Petra Nygren (ORCID: https://orcid.org/0000-0003-1723-3970)
- Helka Göös (ORCID: https://orcid.org/0000-0002-6175-4872)
- Diana Schenkwein (ORCID: https://orcid.org/0000-0002-8854-8585)
- Laura Turunen (ORCID: https://orcid.org/0000-0003-0274-4794)
- Salomé Decombis (ORCID: https://orcid.org/0009-0006-1599-8338)
- Tiina Kasanen (ORCID: https://orcid.org/0000-0002-5408-1948)
- Sara Gandolfi (ORCID: https://orcid.org/0000-0001-6207-4433)
- Aleksandr Ianevski (ORCID: https://orcid.org/0000-0002-7780-482X)
- Hanna Lähteenmäki (ORCID: https://orcid.org/0000-0001-6773-2677)
- Anna Näätänen
- Maija Hollmén (ORCID: https://orcid.org/0000-0002-3250-7653)
- Jonas Bouhlal (ORCID: https://orcid.org/0000-0002-7920-3390)
- Essi Laajala (ORCID: https://orcid.org/0000-0002-3382-7966)
- M Myllymaki
- Jay Klievink (ORCID: https://orcid.org/0000-0002-4081-5840)
- Constantine Mitsiades
- Emma Saarinen
- Satu Mustjoki
- Konstantin Matjusinski
- Seppo Ylä-Herttuala (ORCID: https://orcid.org/0000-0001-7593-2708)
- Dean A Lee
- iCAN Flagship
- Diogo Dias
- Matti Korhonen
Institutions
- Broad Institute (US)
- Oslo University Hospital (NO)
- Nationwide Children's Hospital (US)
- University of Helsinki (FI)
- Harvard University (US)
- University of Turku (FI)
- University of Eastern Finland (FI)
- University of Oslo (NO)
- Helsinki University Hospital (FI)
- Finnish Red Cross (FI)
- Wellcome Sanger Institute (GB)
- Kuopio University Hospital (FI)
- Dana-Farber Cancer Institute (US)
- Institute for Molecular Medicine Finland (FI)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-04-17
- DOI
- https://doi.org/10.64898/2026.04.13.717771
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Ida Montinin Säätiö
- Academy of Finland
- Paulon Säätiö
- Ludwig Center at Harvard