A tumor-promoting inflammatory SPP1+ macrophage—IL-6—CRP axis drives immune dysfunction in bladder cancer
Immune checkpoint blockade (ICB) has revolutionized treatment for urothelial bladder cancer (UC), yet response rates remain limited. Inflammation promotes disease progression and treatment resistance, with macrophages shaping the tumor microenvironment (TME). While elevated blood C-reactive protein (CRP) associates with poor clinical outcomes in UC, its relationship to the TME remains unclear. Here, we show that elevated plasma IL-6 and CRP associate with increased tumor macrophage infiltration across multiple ICB-treated cohorts. Single-cell RNA sequencing of the largest UC atlas to date, integrated with bulk RNA sequencing, identifies enrichment of immunosuppressive SPP1+ macrophages in TMEs from patients with high plasma IL-6. Spatial and functional analyses demonstrate that SPP1+ macrophages suppress T cell activity partly via IL-6 signaling, whereas CXCL9+ macrophages promote T cell activation. These findings link systemic inflammation to local immune dysfunction and define a macrophage-driven axis associated with ICB resistance and therapeutic targets to improve immunotherapy outcomes in UC.
Authors
- D. Youssef
- Sanjeev Mariathasan (ORCID: https://orcid.org/0000-0001-5034-773X)
- Sudeh Izadmehr (ORCID: https://orcid.org/0000-0001-8948-5689)
- Reza Mehrazin (ORCID: https://orcid.org/0009-0007-8648-0410)
- Kristin G. Beaumont (ORCID: https://orcid.org/0000-0003-3075-9977)
- Romain Banchereau (ORCID: https://orcid.org/0000-0001-6916-6445)
- Saad Atiq (ORCID: https://orcid.org/0000-0002-1026-9017)
- Kobe Yuen (ORCID: https://orcid.org/0000-0001-8780-341X)
- Sreekumar Balan (ORCID: https://orcid.org/0000-0002-2092-5145)
- Sayali Onkar (ORCID: https://orcid.org/0000-0002-5890-290X)
- S. J. Ben Yoo (ORCID: https://orcid.org/0000-0002-7420-1871)
- Aparna Ananthanarayanan (ORCID: https://orcid.org/0000-0003-4776-9952)
- Jonathan F. Anker (ORCID: https://orcid.org/0000-0002-2918-0346)
- Adam M. Farkas (ORCID: https://orcid.org/0000-0002-5813-9473)
- Monica Garcia-Barros
- Byuri Angela Cho
- Mesude Bicak (ORCID: https://orcid.org/0000-0002-4546-9801)
- M. Tran (ORCID: https://orcid.org/0000-0002-1797-7825)
- Amir Horowitz
- Pedro C. Barata
- Aparna Chhibber
- Diego Chowell
- Nina Bhardwaj
- A. Elliott
- Li Wang
- Sacha Gnjatic
- Saurabh Gupta
- John P. Sfakianos
- Edgar Gonzalez-Kozlova
- Matthew D. Galsky
- Igor Figueiredo
- Karen Lee
- Carlos Cordon-Cardo
- Seunghee Kim-Schulze
- Rana R. McKay
- Tolulope T. Adeyelu
- Ziao Li
- Rachel Brody
Institutions
- Seoul National University (KR)
- Bristol-Myers Squibb (Germany) (DE)
- Seoul National University of Education (KR)
- Samsung Medical Center (KR)
- Stamford Hospital (US)
- New Generation University College (ET)
- University of California San Diego (US)
- Bristol-Myers Squibb (United States) (US)
- Mount Sinai Hospital (US)
- University Hospitals Seidman Cancer Center (US)
- Interdisciplinary Dental Education Academy (US)
- Bristol-Myers Squibb (United Kingdom) (GB)
- Bristol-Myers Squibb (Sweden) (SE)
- Kaiser Permanente South San Francisco Medical Center (US)
- Caris Life Sciences (United States) (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2026-02-26
- DOI
- https://doi.org/10.1158/2159-8290.cd-25-1774
- Primary Topic
- Bladder and Urothelial Cancer Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00