Targeting the CD44-SPP1 Axis: A New Frontier in Bladder Cancer Resistance

At the intersection of immunology and genitourinary oncology, researchers are uncovering how the tumor microenvironment (TME) dictates clinical outcomes. Hiba Siddiqui, BSc, and her team at Dana-Farber Cancer Institute are investigating a critical signaling axis involving the surface protein CD44 and the macrophage-derived cytokine SPP1 in bladder and prostate cancers.

Findings from this research presented at the 2026 American Association for Cancer Research (AACR) Annual Meeting showed how the interaction between CD44 and macrophage-released SPP1 contributes to heightened disease progression and therapy resistance. According to Siddiqui, the study is particularly relevant for stage IV bladder cancer, where high levels of SPP1-positive macrophage infiltration have been identified as a hallmark of late-stage, treatment-resistant disease.

By characterizing this TME heterogeneity, the project aims to identify therapeutic strategies to disrupt this axis or repolarize macrophages. This work could provide a potential roadmap for overcoming the adverse effects of tumor-driven immune evasion and improving advocacy for patients with these advanced malignancies.

Transcript:

The project that I am currently focused on is surrounding the TME, specifically in bladder and prostate cancer. What I am studying is the effect of a surface protein on bladder cancer cells known as CD44, how that interacts with a cytokine released by macrophages known as SPP1, and how this interaction can potentially increase the progression of cancer or increase therapy resistance. We are exploring that axis [and] seeing how we can eliminate it and polarize it to advocate for our patients.

Every patient has a very different tumor profile, with [patients with] stage IV cancer having a very different tumor heterogeneity landscape than someone who has stage I cancer. What we found that precedes a lot of our findings, and the inspiration for our project, is that [patients with] stage IV disease who are in late-stage bladder cancer that have therapy resistance are enriched with SPP1-positive macrophages. This was found in a study by Filipe L. De Carvalho, MD, PhD, and is currently undergoing publication in Immunity. This is the landscape of patients that we have used for this testing that exhibit high levels of SPP1 macrophage infiltration.

Reference

Siddiqui H, Zhou Y, Lee J, et al. Targeting the CD44-SPP1 axis to overcome therapy resistance in bladder cancer. Presented at the 2026 American Association for Cancer Research Annual Meeting; April 17-22, 2026; San Diego, CA. Abstract 3458.