Role of Pirfenidone in Autoimmune Disorders and ImmunoOncology: AComprehensive Review

Abstract

Background: Pirfenidone, originally developed as an antifibrotic agent for idiopathic pulmonary fibrosis (IPF), has emerged as a pro mising therapeutic candidate with pleiotropic immunomodulatory properties that extend beyond its established pulmonary indication. Objective: This review aims to systematically examine the detailed molecular mechanisms underlying pirfenidone's antifibrotic , anti inflammatory, and immunomodulatory activities across key signaling pathways including TGF β/SMAD, NF κB, JAK/STAT, and PI3K/Akt; critically evaluate preclinical and clinical evidence for pirfenidone in autoimmune diseases particularly systemic scler osis, rheumatoid arthritis, lupus nephritis, and inflammatory bowel disease; assess its emerging role in immuno oncology through modulation of the tumor microenvironment; and contextualize pirfenidone within the broader landscape of antifibrotic and immuno modulatory therapies through comparative analysis with nintedanib, mycophenolate mofetil, methotrexate, and targeted biologics. Methods: A comprehensive search of PubMed, ClinicalTrials.gov, Embase, and major conference proceedings (through 2025) was condu cted. Preclinical studies, randomized controlled trials, observational studies, and phase I III clinical trial reports were included and critically appraised. Results: Pirfenidone exerts antifibrotic effects primarily through inhibition of TGF β1 induced S MAD2/3 phosphorylation and suppression of connective tissue growth factor (CTGF) expression, while anti inflammatory properties are mediated through NF κB pathway blockade, modulation of the JAK2/STAT3 axis, and suppression of TNF α, IL 1β, IL 6, and IL 13 . In autoimmune diseases, the LOTUSS Phase 2 trial confirmed tolerability in systemic sclerosis associated ILD, with ongoing SLS III (NCT03221257) examining combination with mycophenolate mofetil. In rheumatoid arthritis, pirfenidone inhibits synovial fibr oblast activation via JAK2/STAT3 and Akt pathways. In immuno oncology, pirfenidone targets cancer associated fibroblasts (CAFs), reduces desmoplastic stroma, enhances CD8+ T cell tumor infiltration, and demonstrates synergy with immun e checkpoint inhibitor s in preclinical pancreatic, colorectal, and non small cell lung cancer models. Compared to nintedanib currently the only other dual approved antifibrotic pirfenidone offers distinct mechanistic advantages, including direct cytokine pathway modulation and superior CAF inhibitory effects. Conclusion: Pirfenidone represents a compelling drug repositioning candidate with a mechanistic rationale spanning autoimmune fibroinflammatory diseases and immuno oncology. Ongoing and planned clinical trials are expected to define its role within evolving therapeutic algorithms. Integration of predictive biomarkers and rational combination strategies will be critical to realizing its full therapeutic potential.