Macrophages in Tumors and Lineage Flexibility in Prostate Cancer

Overview

This review discusses the role of tumor-associated macrophages (TAMs) in influencing lineage plasticity in prostate cancer, particularly in the context of therapy resistance. It highlights emerging evidence linking TAM heterogeneity to aggressive disease states such as neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer (DNPC).

Background

Prostate cancer is a leading cause of cancer-related morbidity and mortality in men. Despite advancements in treatment, including androgen receptor signaling inhibitors, resistance often develops, leading to challenging disease states that are less responsive to conventional therapies. Understanding the role of the tumor microenvironment, particularly TAMs, is crucial for addressing therapy resistance.

Data Highlights

No numerical data or trial data presented in the article.

Key Findings

• TAMs exhibit significant heterogeneity and can influence tumor-cell state transitions and immune exclusion.
• Established myeloid programs include SPP1+/TREM2+ macrophage states and pathways such as IL-6/STAT3 and TGF-beta.
• Emerging frameworks suggest that PLAC8+ TAMs may be linked to ARSI-induced DNPC-like remodeling.
• Spatial transcriptomic technologies reveal non-random neighborhoods involving TAMs and other tumor microenvironment components.
• The proposed TNFAIP8L2-integrin/PI3K-Akt/beta-catenin/FOSL1-HMGA1 cascade requires further validation.

Clinical Implications

The findings indicate the potential for TAMs to be a focus in managing therapy-resistant prostate cancer, emphasizing the need for independent cohort validation and biomarker-guided clinical testing.

Conclusion

The review highlights the role of TAMs in prostate cancer lineage plasticity and therapy resistance, emphasizing the importance of validating proposed mechanisms.

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