Stephanie S Watowich | PubMed Health

PubMed2026

First-line fecal microbiota transplantation for the management of immune checkpoint inhibitor-mediated diarrhea and colitis.

Immune checkpoint inhibitor (ICI) therapy commonly leads to adverse events such as ICI-mediated diarrhea and colitis (IMDC). Fecal microbiota transplantation (FMT) remains an option for patients with refractory colitis. We report a multi-omics profiling of patients receiving first-line FMT for IMDC. In our preliminary analysis, 10 (76.9%) patients achieve clinical response, with a median time to clinical improvement of 1.5 (1-10.5) days. Among responder patients with baseline and follow-up samples, 6 (75%) show an increase in alpha-diversity post-FMT. Pre-FMT samples show an increase in the abundance scores of plasma cells, neutrophils, macrophages (M1 and M2), memory activated and resting memory CD4+ T cells, CD8+ T cells, T follicular helper (Tfh) cells, and regulatory T cells (Tregs), all of which decrease post-FMT. In a small cohort of patients, we identify potential mechanisms for FMT response and demonstrate that first-line FMT in patients with IMDC (NCT04038619) can be effective.

FMT↗

PubMed2025

Cancer-induced nerve injury promotes resistance to anti-PD-1 therapy.

Perineural invasion (PNI) is a well-established factor of poor prognosis in multiple cancer types1, yet its mechanism remains unclear. Here we provide clinical and mechanistic insights into the role of PNI and cancer-induced nerve injury (CINI) in resistance to anti-PD-1 therapy. Our study demonstrates that PNI and CINI of tumour-associated nerves are associated with poor response to anti-PD-1 therapy among patients with cutaneous squamous cell carcinoma, melanoma and gastric cancer. Electron microscopy and electrical conduction analyses reveal that cancer cells degrade the nerve fibre myelin sheets. The injured neurons respond by autonomously initiating IL-6- and type I interferon-mediated inflammation to promote nerve healing and regeneration. As the tumour grows, the CINI burden increases, and its associated inflammation becomes chronic and skews the general immune tone within the tumour microenvironment into a suppressive and exhaustive state. The CINI-driven anti-PD-1 resistance can be reversed by targeting multiple steps in the CINI signalling process: denervating the tumour, conditional knockout of the transcription factor mediating the injury signal within neurons (Atf3), knockout of interferon-α receptor signalling (Ifnar1-/-) or by combining anti-PD-1 and anti-IL-6-receptor blockade. Our findings demonstrate the direct immunoregulatory roles of CINI and its therapeutic potential.

Animals↗