Pan-cancer and single-cell analysis reveal dual roles of lymphocyte activation gene-3 (LAG3) in cancer immunity and prognosis

Q: What is the main goal of this study on LAG3 in cancer?

To explore how LAG3 correlates with cancer-related physiological processes across multiple cancers and to construct LAG3-linked immunity and prognostic models.

Q: How was LAG3 analyzed across pan-cancer datasets?

The study integrates datasets and analytical methods from TCGA, GTE-x and GEO, and uses tools such as cBioPortal, HPA, CellMinerTM and survival-analysis resources to assess expression, infiltration, mutations, methylation, pathways and outcomes.

Q: Does high LAG3 expression always predict better survival?

No. The study reports cancer-type–specific directions: in several cancers high LAG3 correlates with longer overall survival, while in other cancers high LAG3 corresponds to shorter overall survival.

Sep 21, 2026

Uploaded by Rowan

Lymphocyte activating gene-3 (LAG3) is presented as a distinctive T-cell co-receptor with inhibitory immune-checkpoint features. The study investigates links between LAG3 and cancer-related physiological processes across many cancer types, and builds LAG3-associated immunity and prognostic models. Using TCGA, GTE-x, GEO, cBioPortal, HPA, Kaplan-Meier Plotter, and cell and gene analysis tools, the work evaluates expression patterns, tumor-cell localization, immune and matrix infiltration, mutations, DNA methylation, pathways, and drug interactions. Results show cancer-type–specific expression and survival associations, plus ties to immune infiltration, immune subtypes, MSI/TMB/MMR, and T-cell exhaustion.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages17

Reading Time43 min

AccessFree to download

Overview

Study aim and approach

Pan-cancer findings

Expression across tumor types

Survival association (OS and RFS)

Immunological and molecular associations

Immune and stromal scores, immune subtypes

MSI, TMB, MMR and signaling pathways

Drug and biomarker relevance

Drug sensitivity associations

Dual roles in clinical/immune prognostication

[www. nature.com/scientificreports](www. nature.com/scientificreports) OPEN Pan-cancer and single-cell analysis reveal dual roles of lymphocyte activation gene-3 (LAG3) in cancer immunity and prognosis Yongfeng Wang1,2,3,4, Yanzong Zhao5, Guangming Zhang1, Yifeng Lin1, Chunling Fan6, Hui Wei5, Shude Chen7, Ling Guan5, Kan Liu7, ShenhanYu5, Liangyin Fu1,2,3,4, Jing Zhang1, Yuan Yuan3,4􀀍, Jin He1,2,3,4􀀍 & Hui Cai1,2,3,4􀀍 Lymphocyte activating gene-3 (LAG3) is a distinctive T cell co-receptor that is expressed on the surface of lymphocytes. It plays a special inhibitory immune checkpoint role due to its unique domain and signaling pattern. Our aim is to explore the correlation between LAG3 in cancers and physiological processes related to a range of cancers, as well as build LAG3-related immunity and prognostic models. By comprehensively using of datasets and methods from TCGA, GTE-x and GEO databases, cBioPortal, HPA, Kaplan-Meier Plotter, Spearman, CellMinerTM, we delved deeper into the potential impact of the LAG3 in cancer development. These include expression differences, Localization of tumor cell subsets, immune infiltration, matrix infiltration, gene mutations, DNA methylation, signaling pathways and prognosis. Furthermore, we explored LAG3 interactions with different drugs. LAG3 is highly expressed inACC (p < 0.001), BRCA (p < 0.001), DLBC (p < 0.001), ESCA (p < 0.001), GBM (p < 0.001), HNSC (p < 0.001), KIRC (p < 0.001), LGG (p < 0.001), LUAD (p < 0.01), LUSC (p < 0.001), PAAD (p < 0.001), PCPG (p < 0.01), SKCM (p < 0.001), STAD (p < 0.001), TGCT (p < 0.001) and THCA (p < 0.05), while lowly expressed in COAD (p < 0.001), LIHC (p < 0.05), OV (p < 0.001), PRAD (p < 0.001), READ (p < 0.001), UCEC (p < 0.001) and UCS (p < 0.001) . High expression of LAG3 correlates with longer overall survival (OS) in BLCA (HR = 0.67, p < 0.05), CESC (HR = 0.3, p < 0.001), HNSC (HR = 0.67, p < 0.01), LUSC (HR = 0.71, p < 0.05), OV (HR = 0.65, p < 0.01), STAD (HR = 0.68, p < 0.05), and UCEC (HR = 0.57, p < 0.01). Conversely, in KIRC (HR = 1.85, p < 0.001), KIRP (HR = 2.81, p < 0.001), and THYM (HR = 8.92, p < 0.001), high LAG3 expression corresponds to shorter OS. Comprehensive results for recurrence-free survival (RFS) indicate that LAG3 acts as a protective factor in BLCA, CESC, OV, and UCEC. Moreover, LAG3 is widely expressed in tumor-associated lymphocytes, positively correlating with tumor immune scores and stromal scores, and significantly present in the C2 immune subtype across various tumors. High LAG3 expression correlates with increased immune infiltration. LAG3 shows associations with MSI, TMB, and the MMR system, participating in multiple signaling pathways including the T cell receptor pathway. It also demonstrates positive correlations with sensitivity to eleven different drugs. Unlike traditional inhibitory immune checkpoints, LAG3 exhibits dual roles in clinical and immune prognostication across pan-cancers, making it a significant predictive factor. In some cancers, LAG3 serves as a risk factor, indicating adverse clinical outcomes. Conversely, in BLCA, CESC, OV, and UCEC, LAG3 acts as a protective factor associated with longer patient survival. LAG3 demonstrates strong associations within tumor immunity, participating in a range of immune and inflammatory signaling pathways. Elevated levels of LAG3 are linked not only toT cell exhaustion but also to increased immune infiltration and polarization towards M1 macrophages. Keywords LAG3, Immune checkpoint, CD8+T cell, Pan-cancer, Prognosis 1The First Clinical Medical College of Lanzhou University, Lanzhou 730000, Gansu, China. 2General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu, China. 3Key Laboratory of Molecular Diagnosticsand Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, 204 Donggang West Road, Lanzhou 730000, Gansu, China. 4NHC Key Laboratory of Diagnosis and Therapy of Gastroint

FAQs

What is the main goal of this study on LAG3 in cancer?

To explore how LAG3 correlates with cancer-related physiological processes across multiple cancers and to construct LAG3-linked immunity and prognostic models.

How was LAG3 analyzed across pan-cancer datasets?

The study integrates datasets and analytical methods from TCGA, GTE-x and GEO, and uses tools such as cBioPortal, HPA, CellMinerTM and survival-analysis resources to assess expression, infiltration, mutations, methylation, pathways and outcomes.

Does high LAG3 expression always predict better survival?

No. The study reports cancer-type–specific directions: in several cancers high LAG3 correlates with longer overall survival, while in other cancers high LAG3 corresponds to shorter overall survival.

Sep 21, 2026

Uploaded by Rowan