Immune Activation Signatures Associated with Fatigue in Cancer Patients Undergoing Immune Checkpoint Inhibitor Therapy

Howard L. Li(Johns Hopkins University), Soren Charmsaz(Johns Hopkins University), Mari Nakazawa(Johns Hopkins University), Stephanie Alden(Memorial Sloan Kettering Cancer Center), Madelena Brancati(Johns Hopkins University), James M. Leatherman(Johns Hopkins University), Ervin Griffin(Johns Hopkins University), Hua‐Ling Tsai(Johns Hopkins University), Nicole Groß(Johns Hopkins University), Christopher J. Thoburn(Johns Hopkins University), Alexei Hernandez(Johns Hopkins University), Erin M. Coyne(Johns Hopkins University), Sarah M. Shin(Johns Hopkins University), Royce P. Lee(Johns Hopkins University), Evan J. Lipson(Johns Hopkins University), Burles A. Johnson(Johns Hopkins University), Aliyah Pabani(Johns Hopkins University), Yasser Ged(Johns Hopkins University), Marina Baretti(Johns Hopkins University), Julie R. Brahmer(Johns Hopkins University), Jean Hoffman‐Censits(Johns Hopkins University), Tanguy Y. Seiwert(Johns Hopkins University), Daniel J. Zabransky(Johns Hopkins University), Jennifer N. Durham(Johns Hopkins University), Elizabeth M. Jaffee(Johns Hopkins University), G. Scott Chandler(Roche (Switzerland)), Brittany L. Adler(Johns Hopkins University), Won Jin Ho(Johns Hopkins University), Chester Kao(Johns Hopkins University), Mark Yarchoan(Johns Hopkins University)
Cancer Research Communications
September 15, 2025
10.1158/2767-9764.crc-25-0240
Cited by 4Open Access
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Abstract

Fatigue is a common and often debilitating adverse event among patients receiving immune checkpoint inhibitor (ICI) therapy, yet its underlying immunologic mechanisms remain poorly defined. We prospectively collected clinical data and blood samples from patients with solid tumors receiving ICI therapy. Patients were prospectively surveyed at month 2, 4, or 6 on treatment to assess for the presence and severity of fatigue as compared with treatment baseline. We analyzed peripheral lymphocyte populations by cytometry by time of flight and peripheral levels of 39 cytokines with a Luminex multiplex assay to identify dynamic immune changes associated with ICI-related fatigue. Of 53 patients enrolled, 31 (58.5%) reported worsening fatigue during ICI therapy. Patients reporting fatigue exhibited broad early-treatment elevations in circulating cytokines, with the most prominent increases observed in the Th1-associated cytokine cluster, including IFN-γ, IL-2, and IL-12. In parallel, several clusters of cytotoxic effector CD8+ T cells expanded significantly from baseline in the fatigued group. Fatigue was not associated with objective tumor response or with the development of other clinically meaningful immune-related adverse events. In a pan-tumor cohort treated with ICIs, increases in clusters of cytotoxic effector CD8+ T cells in parallel with related Th1-associated cytokines were associated with ICI-related fatigue, implicating fatigue as a potential marker of immune activation in this population. SIGNIFICANCE: This study illuminates dynamic changes in peripheral cytokines and immune cell clusters that are associated with ICI-related fatigue. Namely, this study implicates the Th1 pathway as a novel contributor to ICI-related fatigue and identifies ICI-related fatigue as a clinical surrogate for immune activation in patients receiving ICI therapy. Recognizing that fatigue may be a biomarker of heightened immune activity influences monitoring strategies and informs supportive care interventions during immunotherapy.

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