Actin dysregulation induces neuroendocrine plasticity and immune evasion: a vulnerability of small cell lung cancer
Small cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options. Capping protein inhibiting regulator of actin dynamics (CRACD) that promotes actin polymerization, is frequently inactivated in SCLC. However, the role of CRACD loss in SCLC is unknown. Here we show that CRACD depletion drives neuroendocrine (NE) cell plasticity and immune evasion in SCLC. Mechanistically, CRACD inactivation disrupts actin organization, leading to suppression of Yap1-NOTCH signaling and subsequent NE gene upregulation. Simultaneously, CRACD loss drives EZH2-mediated histone methylation via nuclear actin disruption, leading to repression of MHC-I genes and depletion of CD8⁺ T cells. Consequently, CRACD-downregulated tumors exhibit increased cellular heterogeneity and escape from immune surveillance. Conversely, pharmacological inhibition of EZH2 restores MHC-I expression, reactivates antitumor immunity, and suppresses tumor growth. These findings identify CRACD as a tumor suppressor that constrains cell plasticity and immune evasion, highlighting the CRACD-EZH2-MHC-I axis as a potential therapeutic vulnerability in SCLC.
Authors
- Kee‐Beom Kim (ORCID: https://orcid.org/0000-0003-0132-8924)
- Min Gyu Lee (ORCID: https://orcid.org/0000-0003-0859-0642)
- Ye Eun Hwang (ORCID: https://orcid.org/0000-0003-4048-9501)
- Wonhong Chu
- Kyung-Pil Ko (ORCID: https://orcid.org/0000-0002-9554-5972)
- Joseph M. Chan (ORCID: https://orcid.org/0000-0001-5249-7395)
- Yoojeong Seo (ORCID: https://orcid.org/0000-0001-7243-5386)
- Jae‐Il Park (ORCID: https://orcid.org/0000-0002-0737-2654)
- Gengyi Zou (ORCID: https://orcid.org/0000-0002-5399-8674)
- Bong-Jun Kim (ORCID: https://orcid.org/0000-0001-7198-0411)
- Shengzhe Zhang (ORCID: https://orcid.org/0009-0003-9092-4652)
- Nicole Kirk (ORCID: https://orcid.org/0000-0002-3609-5502)
- Young Ho Ban (ORCID: https://orcid.org/0000-0002-1936-204X)
- Charles M. Rudin (ORCID: https://orcid.org/0000-0001-5204-3465)
- Shilpa S. Dhar (ORCID: https://orcid.org/0000-0002-5922-2164)
- Jie Zhang (ORCID: https://orcid.org/0000-0002-5452-1819)
- Sohee Jun (ORCID: https://orcid.org/0009-0006-7259-4735)
- Dong Wook Kim (ORCID: https://orcid.org/0000-0001-6167-6475)
- Yuanjian Huang (ORCID: https://orcid.org/0000-0002-1611-8252)
- Jinho Jang
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Kyungpook National University (KR)
- University of Virginia (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-06
- DOI
- https://doi.org/10.1038/s41467-025-67078-9
- Citations
- 2
- Primary Topic
- Lung Cancer Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 2.09