Preprint / Version 1

The Mevalonate Pathway Drives Tumor Immune Evasion via RalB-Mediated PD-L1 Trafficking

This article is a preprint and has not been certified by peer review.

Authors

    Meng Hao,  
    Meng Hao
    Jixing Zhong,   Ying Huang,   Bin Huang,   Weiyao Kong,   Yi Wang,   Dan Luo,   Yu Zhang,   Hui Wang,   Yi Zhou,   Ying He,   Juyuan Wang,   Yong Nian,  
    Yong Nian
    Lei Zhang,  
    Lei Zhang
    Chengqian Yin
    Chengqian Yin
Categories
Cell Biology
Keywords
PD-L1; Mevalonate Pathway; Prenylation; FDPS; Immune Checkpoint Blockade

Abstract

Tumor metabolic rewiring supports malignant growth and can concurrently dampen antitumor immunity, yet how the tumor-intrinsic mevalonate (MVA) pathway enforces immune escape remains insufficiently defined. Here we show that genetic or pharmacologic disruption of the MVA pathway in tumor cells elicits a robust immune response, increasing intratumoral CD8⁺ T cell infiltration and effector function and thereby constraining tumor growth. Mechanistically, we identify farnesyl pyrophosphate synthase (FDPS) as a central metabolic-immune node that modulates the isoprenoid pool, altering levels of geranylgeranyl pyrophosphate (GGPP) and consequently the geranylgeranylation status of the small GTPase RalB. RalB geranylgeranylation in turn exerts dual control of tumor cell PD-L1, promoting PD-L1 surface availability through regulation of protein trafficking while also augmenting PD-L1 expression at the transcriptional level. Therapeutically, inhibition of FDPS using clinically established nitrogen-containing bisphosphonates potentiates PD-1/CTLA-4 blockades and yields marked antitumor activity in vivo. Collectively, these findings define a tumor-intrinsic MVA-GGPP-RalB axis that drives PD-L1-dependent immune evasion and provide a mechanistic rationale for repurposing nitrogen-containing bisphosphonates as rational combinatorial agents to improve the efficacy of immune checkpoint blockade

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DOI:

https://doi.org/10.65215/LTSpreprints.2026.01.30.000114

Submission ID:

114

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Posted

2026-01-30

How to Cite

Hao, M., Zhong, J., Huang, Y., Huang, B., Kong, W., Wang, Y., Luo, D., Zhang, Y., Wang, H., Zhou, Y., He, Y., Wang, J., Nian, Y., Zhang, L., & Yin, C. (2026). The Mevalonate Pathway Drives Tumor Immune Evasion via RalB-Mediated PD-L1 Trafficking. LangTaoSha Preprint Server. https://doi.org/10.65215/LTSpreprints.2026.01.30.000114

Declaration of Competing Interests

The authors declare no competing interests to disclose.

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