Glioma-intrinsic MAPK/ERK signaling promotes immunotherapy efficacy through T cell infiltration and interferon responses
Abstract Glioblastoma (GBM) remains a formidable challenge in neuro-oncology, with immune checkpoint blockade (ICB) only showing efficacy in some patients, while the mechanisms governing therapeutic responsiveness are poorly defined. Although MAPK/ERK signaling correlates with survival following ICB, its causal role and mechanisms underlying tumor immunogenicity remain unclear. Here, we perform in vivo kinome-wide CRISPR/Cas9 screens in murine gliomas where we identify RAF-MEK-ERK axis as the strongest modulators of glioma susceptibility to anti-programmed cell death protein 1 (anti-PD-1) therapy and CD8 + T cell recognition. Experimentally-induced ERK phosphorylation (p-ERK) enhances survival after anti-PD-1 and anti-CTLA-4 therapy, leading to durable antitumor immunity upon rechallenge. Additionally, glioma cell p-ERK promotes increased interferon responses and T cell infiltration. Notably, BRAF/MEK inhibition disrupts interferon programs and tumor-microglia interactions in BRAF V600E ex vivo in human GBM/brain slice cultures. Our findings elucidate that tumor-intrinsic MAPK/ERK promotes immunotherapy response, interferon responses, T cell tumor infiltration, and GBM cell-microglia interactions.
Authors
- Junfei Zhao (ORCID: https://orcid.org/0000-0002-4569-9797)
- Wenting Zhao (ORCID: https://orcid.org/0000-0002-6143-5185)
- Catalina Lee-Chang (ORCID: https://orcid.org/0000-0002-7675-2124)
- Crismita Dmello (ORCID: https://orcid.org/0000-0002-1688-9663)
- Peter Canoll (ORCID: https://orcid.org/0000-0002-7001-0226)
- Raúl Rabadán (ORCID: https://orcid.org/0000-0001-7946-9255)
- Adam M. Sonabend (ORCID: https://orcid.org/0000-0002-8347-1945)
- Dieter Henrik Heiland (ORCID: https://orcid.org/0000-0002-9258-3033)
- Peter A. Sims (ORCID: https://orcid.org/0000-0002-3921-4837)
- Pouya Jamshidi (ORCID: https://orcid.org/0000-0002-2038-8589)
- Dhan Chand (ORCID: https://orcid.org/0009-0003-8124-4399)
- Jian Hu (ORCID: https://orcid.org/0000-0001-9760-2013)
- Y Yabo
- Junyi Zhang (ORCID: https://orcid.org/0000-0002-0001-2971)
- Bin Zhang (ORCID: https://orcid.org/0000-0002-6631-7647)
- Kwang‐Soo Kim (ORCID: https://orcid.org/0000-0002-6081-9857)
- Si Wang (ORCID: https://orcid.org/0000-0003-4155-0810)
- Rishi Jain (ORCID: https://orcid.org/0000-0003-4459-5504)
- Elena Grabis
- J. A. Duffy
- Surya Pandey
- Karl Habashy
- Víctor A. Arrieta
- Daniel Levey
- Andrew Gould
- Irina Balyasnikova
- Li Chen
Institutions
- Northwestern University (US)
- The University of Texas MD Anderson Cancer Center (US)
- University of Freiburg (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Columbia University Irving Medical Center (US)
- University Medical Center Freiburg (DE)
- Agenus (United States) (US)
- Universitätsklinikum Erlangen (DE)
- Northwestern Medicine (US)
- Comprehensive Cancer Center Erlangen (DE)
- Neurological Surgery (US)
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
- Columbia University (US)
- The University of Texas Health Science Center at Houston (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-06-25
- DOI
- https://doi.org/10.1038/s41467-026-74124-7
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institutes of Health
- National Cancer Institute