How Tumor-Associated Macrophages Facilitate Bladder Cancer’s Escape from the Immune System

Bladder cancer remains a major challenge due to its tendency to recur and its resistance to treatments, particularly immunotherapies targeting PD-1 or PD-L1. Yet, fewer than a quarter of patients respond effectively to these therapies. A recent breakthrough highlights the key role of tumor-associated macrophages, immune cells present in the immediate tumor environment. These macrophages, especially those of the M2 type, are linked to more aggressive disease progression and a poorer response to treatments.

Researchers have discovered that certain macrophages, identified by the presence of the CXCL5 protein, play a dual role. On one hand, they worsen the prognosis by promoting tumor growth, resistance to chemotherapy, and the formation of lung metastases. On the other hand, their presence paradoxically seems to enhance the effectiveness of immunotherapy. This phenomenon is explained by the activation of a specific signaling pathway, called CXCL5-CXCR2, which stimulates the expression of PD-L1 on the surface of cancer cells and macrophages. PD-L1 is a molecule that allows tumor cells to evade immune surveillance by inhibiting the activity of T lymphocytes, cells responsible for destroying abnormal cells.

Macrophages do more than just help the tumor grow. They also modify their environment by secreting substances that attract other suppressive immune cells and by producing metabolites such as kynurenine, which further weaken the immune response. Conversely, this same CXCL5-CXCR2 pathway makes tumors more sensitive to certain immune treatments, as it creates an inflammatory microenvironment conducive to the action of drugs targeting PD-1 or PD-L1.

Laboratory experiments and animal models have confirmed that blocking CXCL5 or its receptor CXCR2 reduces the ability of cancer cells to migrate, form metastases, and resist immune attacks. These findings suggest that patients whose tumors are infiltrated by CXCL5-expressing macrophages may respond better to immunotherapy, despite generally having a poorer prognosis.

This discovery paves the way for new therapeutic strategies. By specifically targeting the CXCL5-CXCR2 pathway, it may be possible to make tumors more vulnerable to immune defenses and improve the effectiveness of existing treatments. It also underscores the importance of better understanding the complex interactions between tumor cells and their microenvironment to develop personalized approaches against bladder cancer.

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Official Study Source

DOI: https://doi.org/10.1007/s00262-026-04353-8

Title: Multi-omics study on tumor-associated macrophages remodeling the tumor microenvironment via the CXCL5-CXCR2 axis to drive immune escape in bladder cancer

Journal: Cancer Immunology, Immunotherapy

Publisher: Springer Science and Business Media LLC

Authors: Yunzhong Jiang; Jianpeng Li; Zezhong Yang; Minghai Ma; Lu Wang; Lu Zhang; Minxuan Jing; Yaodong Zhang; Yuanchun Pu; Yutong Chen; Jiale He; Hang Liu; Xiaowei Qu; Mengzhao Zhang; Jinhai Fan