ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
This article is part of the Research TopicImmunotherapy Resistance in Solid Tumor: Intrinsic Characteristics of Cancer Cells and Tissue Microenvironment FactorsView all 4 articles
FFPE-based Proteomics and Machine Learning Reveal Immune Microenvironment Features and Distant Metastasis Risk in N1c Colorectal Cancer
Provisionally accepted
Chenxiao Zheng1Qiongying Zhang2
Peng Li2Haobo Jin3Hangjia Xu1Yating Zheng1Yanyu Chen4Zihan Wang1
Baiwang Zhu1*
Xiaodong Zhang1*
Yifei Pan1*- 1Department of Colorectal Anal Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- 2Department of Pathology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- 3Laboratory Animal Centre, Wenzhou Medical University, Wenzhou, Zhejiang Province, China
- 4Hangzhou Medical College, Hangzhou, Zhejiang Province, China
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Abstract Background Colorectal cancer (CRC) ranks third in global cancer incidence and second in mortality. Tumor deposit (TD), a specific regional spread form, is a crucial independent risk factor for survival and have biological differences from lymph node metastasis (LNM). However, it is underestimated in current staging systems, which results in biased treatment decisions and prognosis evaluation. Moreover, the biological features and distant metastasis patterns of N1c CRC remain largely unknown. Method We performed Data-independent Acquisition Mass Spectrometry (DIA-MS) analysis of formalin-fixed, paraffin-embedded (FFPE) samples from 13 T1-T4N1cM1 CRC patients to reveal their molecular characteristics. 9 machine learning algorithms identified 10 TD-related metastasis genes (TDRGs), the multi-cohort validation in 1,582 CRC patients confirmed their role in prognosis. Immune landscape and immunotherapy response were assessed by the CIBERSORT, tumor mutation burden (TMB), Tumor Immune Dysfunction and Exclusion (TIDE) score, Consensus molecular subtype (CMS), immune checkpoint gene expression. scRNA-seq analysis identified Procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase 1 (PLOD1) expression in CRC, Immunohistochemical staining (IHC) and Masson's trichrome staining were used to assess PLOD1 expression and collagen fiber content in CRC, its role in tumor invasion and migration was elucidated by wound healing and transwell assays. Results
Keywords: colorecatal cancer, Immunotherapy response, metastasis, PLOD1, tumor deposit
Received: 08 Mar 2025; Accepted: 16 Jan 2026.
Copyright: © 2026 Zheng, Zhang, Li, Jin, Xu, Zheng, Chen, Wang, Zhu, Zhang and Pan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Baiwang Zhu
Xiaodong Zhang
Yifei Pan
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