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

## TL;DR

Lenvatinib improves the effectiveness of radiotherapy and PD-L1 immunotherapy in lung adenocarcinoma by modulating immune and vascular responses.

## Contribution

This study demonstrates Lenvatinib's novel role in enhancing antitumor effects through dual immune-vascular modulation in lung adenocarcinoma.

## Key findings

- Lenvatinib suppressed radiation-induced PD-L1 and VEGFR2 expression and inhibited angiogenesis.
- Triple-combination therapy extended median survival and enhanced CD8+ T-cell infiltration and M1 macrophage polarization.
- Lenvatinib reduced regulatory T cells and microvessel density in the tumor microenvironment.

## Abstract

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

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.

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.

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