Leveraging the CD44-SPP1 Axis in Muscle-Invasive Bladder Cancer

The tumor microenvironment (TME) is no longer viewed as a passive backdrop to oncogenesis but as a dynamic orchestrator of therapeutic failure. At the 2026 American Association for Cancer Research (AACR) Annual Meeting, Hiba Siddiqui, BSc, shared insights into a specific signaling pathway that governs this resistance in bladder and prostate cancers: the CD44-SPP1 axis. This interaction between the CD44 surface protein on tumor cells and SPP1-positive macrophages appears to be a critical driver of the M2 macrophage polarization that shields malignant cells from cytotoxicity.

Siddiqui highlighted a key finding in her research that showed patients with stage IV bladder cancer exhibit a marked enrichment of these immunosuppressive macrophages, correlating directly with cisplatin resistance and poor clinical outcomes. By elucidating this axis, her team is paving the way for novel interventions, including engineered CAR macrophage therapies designed to re-sensitize the TME. These findings suggest that by "re-programming" the TME, clinicians may finally be able to dismantle the biological barriers to standard-of-care efficacy.

In this interview with CancerNetwork®, Siddiqui discussed the spatial signatures of late-stage disease, the potential for CD44-SPP1 blockade as a priming strategy, and the rigorous evaluation of systemic adverse effects (AEs) in emerging murine models.

CancerNetwork: Can you provide a brief background and overview of your presentation?

Siddiqui: 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, seeing how we can eliminate it and polarize it to advocate for our patients.

Because the study correlates CD44 and SPP1 expression with cisplatin resistance and poor outcomes, do you envision a spatial signature or expression threshold that could eventually be used in the clinic to pre-select patients for CD44-SPP1 blockade alongside standard-of-care enfortumab vedotin (Padcev) plus pembrolizumab (Keytruda; EV-P)?

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.

Did your research indicate whether the SPP1-mediated immunosuppressive microenvironment or the CD44-SPP1 axis specifically modulates Nectin-4 levels, or does this axis primarily drive resistance through downstream survival signaling?

We haven't looked particularly at Nectin-4, but we do know that the interaction of CD44 and SPP1 could be a cause of macrophage polarization. For example, switching macrophages from an M1 phenotype to an M2 phenotype, or vice versa, [may] create an anti-tumor or anti-inflammatory effect on the environment. Increasing this axis interaction can allow the tumor to be more therapeutically resistant because of the change in macrophage polarization, and that is exactly what we are trying to look into now.

In your murine models, did you observe any significant AEs or systemic toxicities when blocking the CD44-SPP1 axis, particularly when combined with agents like cisplatin or EV?

We have only used cisplatin in anti–PD-1 models that are murine models, specifically, and we haven't seen any obvious effects of systemic, wide toxicity as of right now. However, we are currently in the stages of developing more complex experiments that require increased numbers of mice and arms that would allow us to test this more effectively. We're also using a new method of injecting these macrophages, which is through a tail vein injection method. This is more systemic based, so we would be able to see more systemic effects with this new treatment we plan to use in newer models and newer experiments.

Could you elaborate on the proposed delivery mechanism for the engineered macrophage-based immunotherapies mentioned in the conclusion? How do you ensure they maintain their pro-phagocytic state once they encounter the bladder TME?

We plan to use a multitude of different therapies that are combined with immuno-agents, such as CAR therapies. Specifically, we're looking at CAR macrophage therapies that can allow us to detect specific types of CD44 that are specific to bladder cancer models. We are not entirely sure at this moment how it would pan out and what way we would administer that to patients, but the design for that model and for that mechanism is currently in progress.

Should CD44-SPP1 inhibitors be administered concurrently with chemotherapy or antibody drug conjugates, or is there a biological rationale for using them as a "priming" agent to re-sensitize the TME prior to cytotoxic treatment?

We haven't specifically looked at how to use anti-CD44 and anti-SPP1 antibodies in a clinical context or a solely therapeutic context. It has more so been used in our experiments to elucidate the role of CD44 and SPP1 for us to further our experiments. But given the results that we did see in murine models, there were significant effects of decreasing tumor volume and decreasing therapy resistance with administering anti-CD44 and anti-SPP1 antibodies, so it could be used as a potential therapeutic mechanism for combining with chemotherapy or radiation in a different context.

Are there any other research or presentations you would like to highlight from the conference?

I know that CAR-based immunotherapy is a hot topic right now, and I'm excited to learn more about that at the conference itself. That is one step towards immunotherapy as precision medicine and being able to target specific tumor types and tumor cells with specific heterogeneity based on patients. I think this is where we are headed in our project as well, and I'm excited to see where it leads us.

Is there anything else you would like to discuss that we did not already cover?

A lot of what we talked about was important and engaging, [and] it's important to see how many of these treatments and experiments that we do can be translated to a clinical context as seamlessly as possible. A lot of the work that we do is very mechanistic, and we are trying to find ways to streamline these processes and combine them with existing therapies so that they can reach patients sooner and be effective as well.

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.