Lenvatinib potentiates the antitumor efficacy of combined radiotherapy and PD-L1 blockade in lung adenocarcinoma

  • Cancer Biol Ther. 2026 Dec 31;27(1):2610526. doi: 10.1080/15384047.2025.2610526.
Yudi Liu  1 ,  Ling Xiao  1 ,  Xinyu Nie  2 ,  Jiahua Lyu  3 ,  Chengxi Tang  1 ,  Linjie Li  1 ,  Xue Zhang  1 ,  Tao Li  3 ,  Jianming Huang  4 ,  Shichuan Zhang  3
Affiliations
  • 1. Department of Radiation, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People's Republic of China.
  • 2. The People's Hospital of Kaizhou District, Chongqing, People's Republic of China.
  • 3. Department of Radiation, Radiation Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, People's Republic of China.
  • 4. Biochemistry and Molecular Biology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, People's Republic of China.
PMID: 41481002 DOI: 10.1080/15384047.2025.2610526
Abstract

Background: The potential of Lenvatinib to synergize with combined radiotherapy and immunotherapy in LUAD remains incompletely characterized.

Methods: We investigated Lenvatinib's effects on radiation-induced PD-L1 in LUAD cells and VEGFR2 in HUVECs via Western blot, VEGFA expression via RT-qPCR/ELISA, and angiogenesis via immunofluorescence. LUAD-HUVEC crosstalk was modeled in vitro. In C57BL/6 mice bearing LUAD tumors, we evaluated the efficacy of RT and anti-PD-L1 with or without Lenvatinib, monitoring tumor growth, survival, and profiling the tumor microenvironment by mIHC and flow cytometry.

Results: Lenvatinib suppressed radiation-induced PD-L1 and VEGFR2 expression, inhibited angiogenesis, and disrupted HUVEC-facilitated LUAD proliferation. The triple-combination (RT + anti-PD-L1 + Lenvatinib) significantly suppressed tumor progression (P < 0.05) and extended median survival (34 vs. 29.5 days, P < 0.05) versus dual therapy. It also enhanced intratumoral CD8+ T-cell infiltration and cytotoxicity, promoted M1-like macrophage polarization, and reduced regulatory T cell frequency and microvessel density.

Conclusions: Lenvatinib potentiates RT and anti-PD-L1 therapy in LUAD through dual immune-vascular modulation, supporting the clinical translation of this triple-combination strategy.

Keywords
Lenvatinib; PD-L1; VEGFR2; lung adenocarcinoma; radiotherapy.
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