Journal Article

DKFZ-2026-00876

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Tumor lactate metabolism shapes immune suppression and therapeutic resistance revealed by integrative multi-omics and digital pathology.

Feng, B. ; Zhu, Y. ; Zhang, Z. ; Wang, Y. ; Schuler, P. J. ; Hess, J. (Last author)DKFZ*

2026
Frontiers Media Lausanne

Abstract: Lactate metabolism is a hallmark of cancer metabolic reprogramming, shaping tumor immunity and therapeutic resistance, yet clinically accessible and low-cost methods to assess intratumoral lactate activity remain limited.We curated a lactate-related 59-gene signature and characterized its biological and clinical relevance across TCGA, GEO, and single-cell RNA-seq datasets. By integrating multi-omic, spatial, and computational analyses, we linked lactate metabolism to the tumor microenvironment and developed a deep learning framework to infer lactate metabolic states directly from routine H&E whole-slide images.High lactate activity (LAC_H) was associated with enhanced tumor proliferation, suppressed immune infiltration, and poor response to both immunotherapy and radiotherapy in HNSCC. The pathology-based model achieved robust performance in distinguishing LAC_H from LAC_L tumors (AUC = 0.73-0.82 in HNSCC) and demonstrated strong generalizability across 12 TCGA cancer types (AUC = 0.78-0.89). Importantly, external validation in an independent real-world SAZHU-HNSCC cohort confirmed that model-predicted LAC_H tumors exhibited significantly increased protein expression of LDHA and MCT1 by immunohistochemistry, supporting the biological validity of the digital lactate biomarker.This study integrates multi-omics and digital pathology to infer tumor lactate metabolism from routine histology, providing a scalable and clinically practical digital biomarker for metabolism-informed precision oncology.

Keyword(s): Humans (MeSH) ; Tumor Microenvironment: immunology (MeSH) ; Lactic Acid: metabolism (MeSH) ; Drug Resistance, Neoplasm (MeSH) ; Head and Neck Neoplasms: metabolism (MeSH) ; Head and Neck Neoplasms: therapy (MeSH) ; Head and Neck Neoplasms: immunology (MeSH) ; Head and Neck Neoplasms: pathology (MeSH) ; Head and Neck Neoplasms: genetics (MeSH) ; Squamous Cell Carcinoma of Head and Neck: metabolism (MeSH) ; Squamous Cell Carcinoma of Head and Neck: therapy (MeSH) ; Squamous Cell Carcinoma of Head and Neck: immunology (MeSH) ; Squamous Cell Carcinoma of Head and Neck: pathology (MeSH) ; Squamous Cell Carcinoma of Head and Neck: genetics (MeSH) ; Biomarkers, Tumor: metabolism (MeSH) ; Multiomics (MeSH) ; digital biomarker ; digital pathology ; head and neck squamous cell carcinoma ; lactate metabolism ; metabolic phenotyping ; Lactic Acid ; Biomarkers, Tumor

Note: #LA:E220#

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Contributing Institute(s):

1. E220 Radioonkologie Radiobiologie (E220)

Research Program(s):

1. 315 - Bildgebung und Radioonkologie (POF4-315) (POF4-315)

Appears in the scientific report 2026

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Database coverage:
; ; ; ; Article Processing Charges ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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