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Cancer Discov., Feb 27 2026, | https://doi.org/10.1158/2159-8290.CD-25-1774 A tumor-promoting inflammatory SPP1+ macrophage-IL-6-CRP axis drives immune dysfunction in bladder cancer

Michelle A. Tran ^{a,b #}, Byuri Angela Cho ^{b,c,d #}, Sudeh Izadmehr ^a#, Seong-Keun Yoo ^{b,c,e #}, Dina Youssef ^a,b, Jonathan F. Anker ^a,b, Adam M. Farkas ^a,b, Igor Figueiredo ^b, Karen Lee ^a,b, Aparna Ananthanarayanan ^a,b, Sreekumar Balan ^a,b, Sayali Onkar ^a,b, Romain Banchereau ^f, Saurabh Gupta ^g, Aparna Chhibber^g, Li Wang a,Kristin G. Beaumont ^h, Ziao Li ^a, Monica Garcia-Barros ⁱ, Mesude Bicak ^a, Carlos Cordon-Cardoⁱ, Rachel Brody ⁱ, Seunghee Kim-Schulze ^b, Kobe Yuen ^f, Sanjeev Mariathasan ^f, Saad O. Atiq ^a, Tolulope T. Adeyelu ^j, Andrew Elliott ^j, Pedro Barata ^k, Rana R. McKay ^l, Sacha Gnjatic ^a,b, Edgar Gonzalez-Kozlova ^b, Reza Mehrazin ^m, Amir Horowitz ^b,c, John P. Sfakianos ^m, Diego Chowell ^b,c,*, Matthew D. Galsky ^a,*, Nina Bhardwaj ^a,b,j,*

^aDivision of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
^bDepartment of Immunology & Immunotherapy, The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
^cDepartment of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
^dPresent address: Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea

^ePresent address: Samsung Precision Genome Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

^fGenentech, San Francisco, CA, USA

^gBristol Myers Squibb, Princeton, NJ, USA

^hDepartment of Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

ⁱDepartment of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

^jCaris Life Sciences, Irving, TX, USA

^kSeidman Cancer Center, University Hospitals, Cleveland, OH, USA

^lMoores Cancer Center, University of California San Diego, San Diego, CA, USA

^mDepartment of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

^#These authors contributed equally

^*Corresponding authors: correspondence to Diego Chowell, Matthew D. Galsky or Nina Bhardwaj

Abstract

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.

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