A new review has illuminated a critical but often overlooked dimension of autosomal dominant polycystic kidney disease (ADPKD)—its immune microenvironment. Traditionally regarded as a genetic disorder driven by mutations in the PKD1 and PKD2 genes, ADPKD is now being redefined by the recognition of chronic inflammation, immune cell infiltration, and immune signaling pathways as key contributors to disease progression.

This comprehensive synthesis of current evidence reveals a complex interaction between innate and adaptive immune responses that fosters cyst growth, renal fibrosis, and loss of kidney function. Macrophages—both resident and monocyte-derived—play a particularly dynamic role, with M1-type macrophages fueling inflammation in early disease stages and M2-type macrophages promoting fibrosis in later stages. These immune cells are activated by damage-associated molecular patterns (DAMPs) released from stressed epithelial cells and orchestrate downstream inflammatory cascades through cytokines such as TNF-α, IL-1β, and IL-6.

The review also highlights the role of immune checkpoints, including PD-1/PD-L1 and CTLA-4, which are upregulated in ADPKD kidneys and appear to regulate T cell activity within the cystic milieu. Furthermore, components of the complement system, particularly the alternative complement pathway, are found to be hyperactivated, implicating them in both inflammatory signaling and cyst expansion.

Beyond characterizing these mechanisms, the article explores the therapeutic promise of modulating the immune system. Targeted interventions—ranging from MCP-1 and MIF inhibitors to immune checkpoint blockers and NF-κB/JAK-STAT pathway modulators—have shown efficacy in preclinical models. Compounds like triptolide, resveratrol, and rosmarinic acid are among the agents demonstrating potential to suppress inflammation, inhibit cyst growth, or attenuate fibrosis. Importantly, these therapies reflect a shift from symptom management to immune-targeted disease modification.

The findings redefine ADPKD not just as a structural or genetic disease, but as one deeply intertwined with immune regulation. This paradigm shift opens the door to innovative treatment strategies that may significantly improve long-term outcomes for the millions affected worldwide. As research continues, the immune landscape of the kidney may offer new hope in halting or even reversing this progressive and often debilitating condition.

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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Reference
Cheng Xue, Xinming Li, Chenchen Zhou, Changlin Mei, Zhiguo Mao, Immune microenvironment in autosomal dominant polycystic kidney disease, Genes & Diseases, Volume 13, Issue 2, 2026, 101694, https://doi.org/10.1016/j.gendis.2025.101694

Funding
National Natural Science Foundation of China 82070705
National Natural Science Foundation of China 81770670
National Natural Science Foundation of China 81873595
Shanghai Municipal Key Clinical Specialty (China) shslczdzk02503
Shanghai Science and Technology Talent Program (China) 19YF1450300
Research Projects of Shanghai Science and Technology Committee of China 17411972100
Shanghai Science and Technology Innovation Action Plan of Scientific Instruments and Chemical Reagents Project (China) 24142201800
China Scholarship Council 202408310237