Glioma-intrinsic MAPK/ERK signaling promotes immunotherapy efficacy through T cell infiltration and interferon responses
- Kwang-Soo Kim
- Junyi Zhang
- Víctor A. Arrieta
- Crismita Dmello
- Elena Grabis
- Yahaya A. Yabo
- Si Wang
- Karl Habashy
- Joseph Duffy
- Junfei Zhao
- Andrew Gould
- Rishi Jain
- Li Chen
- Jian Hu
- Irina Balyasnikova
- Dhan Chand
- Daniel Levey
- Peter Canoll
- Wenting Zhao
- Peter A. Sims
- Raul Rabadan
- Surya Pandey
- Bin Zhang
- Pouya Jamshidi
- Catalina Lee-Chang
- Dieter Henrik Heiland
- Adam M. Sonabend
2026-06-25
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.