Heterogeneity of immune checkpoint inhibitor-related inflammatory central nervous system adverse event reporting signals in primary and metastatic brain tumors: a pharmacovigilance study with single-cell and spatial transcriptomic contextualization.

Overview

Authors: Junlin Song¹, Zeyu He¹, Chong Han¹, Xiaohong Hou¹

Department of Neurosurgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China

Institutions: Zunyi Medical University (China); Affiliated Hospital of Zunyi Medical College (China)

Journal: Frontiers in immunology, volume 17, article 1866830

Dates: received 27 April 2026; accepted 23 June 2026; published online 8 July 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.3389/fimmu.2026.1866830 · PMID 42488653 · PMCID PMC13388250 · OpenAlex W7167684494

Open access: gold, a free copy (OpenAlex)

Status: data only

Categories: genetics / omics (modality), human (organism), other condition (population)

Methods: Statistics, Smoothing, state filtering, decompositions, Machine learning, Preprocessing, Connectivity

Keywords: central nervous system immune-related adverse events, immune checkpoint inhibitors, pharmacovigilance, single-cell RNA sequencing, spatial transcriptomics

MeSH: Brain Neoplasms*, Immune Checkpoint Inhibitors*, Adverse Drug Reaction Reporting Systems, Female, Humans, Male, Pharmacovigilance, Single-Cell Analysis, Spatial Transcriptomics, Transcriptome, Tumor Microenvironment (* major topic)

Topic: Cancer Immunotherapy and Biomarkers (Oncology, Medicine), according to OpenAlex

Citations: not cited yet (Europe PMC); 36 references in the paper

Abstract

Background: Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs) across multiple organ systems. Although inflammatory central nervous system irAEs (CNS inflammatory irAEs) are uncommon, they are often severe. Primary CNS tumors and brain metastases have distinct immune microenvironments, yet the heterogeneity of ICI-related inflammatory CNS irAE reporting signals across tumor phenotypes remains poorly understood.

Methods: We used pharmacovigilance signal discovery, external corroboration, and transcriptomic contextualization of pre-existing brain tumor immune landscapes. We constructed an ICI-exposed cohort from the FDA Adverse Event Reporting System (FAERS) and compared inflammatory CNS irAE disproportionality signals across primary CNS tumors, brain metastases, and non-CNS solid tumors. External comparison used the Japanese Adverse Drug Event Report database (JADER). Public single-cell RNA sequencing datasets were analyzed to characterize baseline strict inflammatory and broad stress-related modules across cellular compartments, with spatial transcriptomics used as secondary descriptive visualization in brain metastasis tissue.

Results: In FAERS, inflammatory CNS irAE reporting signals suggested tumor phenotype-associated heterogeneity, with adjusted odds ratios of 1.65 (95% CI, 1.02–2.65) for primary CNS tumors and 3.12 (95% CI, 2.45–3.98) for brain metastases versus non-CNS solid tumors. Signals were stronger under a strict noninfectious phenotype and attenuated under a broad neuroinflammatory phenotype. Thyroid comparator analyses showed no comparable enrichment, whereas the myocarditis-related comparator was too sparse in the brain metastasis subgroup for meaningful inference. JADER showed a broadly similar pattern, although primary CNS tumor estimates were sparse and exploratory. Baseline single-cell analyses localized strict inflammatory module activity mainly to myeloid and T/NK compartments, while spatial maps served only as secondary descriptive visualization.

Conclusions: ICI-related inflammatory CNS irAE reporting signals suggested tumor phenotype-associated differences, most prominently in brain metastases. Stricter phenotype definitions appeared more specific than broader neuroinflammatory definitions. Public single-cell datasets characterized pre-existing immune-rich myeloid/T-NK compartments, while spatial maps provided only secondary descriptive tissue-level visualization and did not demonstrate irAE-onset tissue states. These pharmacovigilance findings should be interpreted as hypothesis-generating reporting associations, not evidence of incidence, absolute risk, or causality.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

geo:GSE131928, at NCBI GEO; found in the text, “Single-cell RNA sequencing analysis”

Data availability statement

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: https://www.ncbi.nlm.nih.gov/, GSE131928 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE131928) https://www.ncbi.nlm.nih.gov/, GSE131907 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE131907) https://www.ncbi.nlm.nih.gov/, GSE179572 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE179572) https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html, N/A https://www.pmda.go.jp/safety/info-services/drugs/adr-info/suspected-adr/0005.html, N/A.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 4 authors, 5 keywords, 11 MeSH terms, 36 references.

Cite

This paper

Song, J., He, Z., Han, C., & Hou, X. (2026). Heterogeneity of immune checkpoint inhibitor-related inflammatory central nervous system adverse event reporting signals in primary and metastatic brain tumors: a pharmacovigilance study with single-cell and spatial transcriptomic contextualization. Frontiers in immunology, 17, 1866830. https://doi.org/10.3389/fimmu.2026.1866830

BibTeX

@article{song2026heterogeneity, author = {Song, Junlin and He, Zeyu and Han, Chong and Hou, Xiaohong}, title = {{Heterogeneity of immune checkpoint inhibitor-related inflammatory central nervous system adverse event reporting signals in primary and metastatic brain tumors: a pharmacovigilance study with single-cell and spatial transcriptomic contextualization}}, journal = {Frontiers in immunology}, year = {2026}, month = jul, volume = {17}, pages = {1866830}, publisher = {Frontiers Media SA}, issn = {1664-3224}, doi = {10.3389/fimmu.2026.1866830}, url = {https://doi.org/10.3389/fimmu.2026.1866830}, pmid = {42488653}, pmcid = {PMC13388250} }

RIS

TY - JOUR AU - Song, Junlin AU - He, Zeyu AU - Han, Chong AU - Hou, Xiaohong TI - Heterogeneity of immune checkpoint inhibitor-related inflammatory central nervous system adverse event reporting signals in primary and metastatic brain tumors: a pharmacovigilance study with single-cell and spatial transcriptomic contextualization T2 - Frontiers in immunology J2 - Front Immunol PY - 2026 DA - 2026/07/08 VL - 17 SP - 1866830 SN - 1664-3224 PB - Frontiers Media SA DO - 10.3389/fimmu.2026.1866830 UR - https://doi.org/10.3389/fimmu.2026.1866830 LA - en ER -

CSL-JSON

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