Promising therapeutic efficacy and safety of a novel integrin α6-targeting peptide-drug conjugate in lung adenocarcinoma

作者：Wuyou Gao, Qiao-Li Wang, Sam Fong Yau Li, Wanqi Chen, Bin Luo, Kaili Xie, Huaze Liao, Leqi Zhong, Youfang Chen, Zhesheng Wen, Guo‐Kai Feng · 发表于：Molecular Cancer · 年份：2025 · DOI：10.1186/s12943-025-02395-7 · 被引用次数：7 · 研究领域：Cell Adhesion Molecules Research、Peptidase Inhibition and Analysis、Immunotherapy and Immune Responses

BACKGROUND: Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer, with poor prognosis due to rapid tumor growth and resistance to current treatments. Thus, the identification of novel biomarkers and therapeutic strategies has become increasingly important in the management of LUAD. METHODS: A novel integrin α6-targeting peptide-drug conjugate, RWYD-MMAE, was designed to increase therapeutic precision and minimize off-target effects. Integrin α6 expression was examined in LUAD tissues and cell lines. The antitumor activity and safety of RWYD-MMAE for LUAD treatment were assessed in vitro and in vivo. Moreover, the combination of RWYD-MMAE with an anti-PD-1 monoclonal antibody was further investigated to elucidate the synergistic therapeutic effects. RESULTS: Integrin α6 was overexpressed in LUAD cells and tissues, suggesting that integrin α6 is a promising target of drug action for LUAD patients. RWYD-MMAE exhibited targeted antitumor activity in LUAD cell lines via G2 phase arrest and apoptosis. Notably, the antitumor efficacy of RWYD-MMAE was positively correlated with ITGA6 expression levels. In vivo experiments indicated that RWYD-MMAE significantly suppresses tumor growth with no detectable systemic toxicity. In addition, RWYD-MMAE was able to ameliorate the tumor immunosuppressive microenvironment and sensitized tumors to immunotherapy, thereby achieving a more pronounced therapeutic response when combined with anti-PD-1 immunotherapy. CONCLUSION: The ...