Proteomics and single cell profiling identify keratin driven preexisting immunity influences lung squamous carcinoma neoadjuvant therapy

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters Pub Date : 2025-08-22 DOI:10.1016/j.canlet.2025.218000

Jiangnan Zhao , Mo Shen , Xia Xu , Shunxian Ji , Shumin Xu , Lei Xu , Ying Yang , Minhua Ye , Yunkun Lu , Pingli Wang , Kai Wang

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引用次数: 0

Abstract

Lung squamous cell carcinoma (LUSC) demonstrates heterogeneous responses to neoadjuvant immune checkpoint blockade, necessitating biomarkers for outcome prediction. Here, we identify tumor keratinization as a key determinant of therapeutic resistance. In 470 LUSC patients, elevated serum CYFRA 21-1 correlated with non-complete pathological response (non-CPR), while CK5/6 immunohistochemistry revealed strong association between keratinization and residual tumor burden. Proteomic profiling of 167 treatment-naïve biopsies stratified patients into distinct subtypes based on keratinization levels. KRT_L (low keratinization) exhibited enhanced immune infiltration, a markedly lower residual viable tumor percentage (P < 0.001), and superior survival outcomes (, P = 0.034) compared to the KRT_H (high keratinization). Conversely, KRT_H displayed upregulation of keratin proteins, activation of metabolic pathways, and enhanced cancer stemness features, alongside notable immunosuppression. Single-cell RNA analysis confirmed higher keratinization, metabolism and stemness in non-CPR tumors, with trajectory analysis linking undifferentiated states to keratin overexpression. Through integrated proteomic and single-cell analyses, our findings establish keratinization as a hallmark of immune-cold LUSC microenvironments, mechanistically linking elevated keratin expression with both stemness features and impaired immunotherapy efficacy, proposing keratin-based stratification for personalized therapy.

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蛋白质组学和单细胞谱鉴定角蛋白驱动的预先存在的免疫影响肺鳞癌新辅助治疗

肺鳞状细胞癌（LUSC）表现出对新辅助免疫检查点阻断的异质反应，需要生物标志物来预测结果。在这里，我们确定肿瘤角化是治疗耐药性的关键决定因素。在470例LUSC患者中，血清CYFRA 21-1升高与非完全病理反应（non-CPR）相关，而CK5/6免疫组化显示角化与残留肿瘤负荷之间存在强相关性。167例treatment-naïve活检的蛋白质组学分析将患者分层为基于角化水平的不同亚型。与KRT_H（高角化）相比，KRT_L（低角化）表现出增强的免疫浸润，显着降低残留活肿瘤百分比（P < 0.001）和更好的生存结果（P = 0.034）。相反，KRT_H表现出角蛋白的上调、代谢途径的激活、癌症干细胞特征的增强，以及显著的免疫抑制。单细胞RNA分析证实了非cpr肿瘤中较高的角化、代谢和干性，轨迹分析将未分化状态与角蛋白过表达联系起来。通过综合蛋白质组学和单细胞分析，我们的研究结果确定角化是免疫冷LUSC微环境的标志，将角蛋白表达升高与干性特征和免疫治疗效果受损机械地联系起来，提出了基于角蛋白的个性化治疗分层。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer letters 医学-肿瘤学

CiteScore

17.70

自引率

2.10%

发文量

427

审稿时长

15 days

期刊介绍： Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.