Objective:

To synthesize evidence linking tumor-associated macrophage (TAM) heterogeneity to lineage plasticity in prostate cancer and to propose a framework for understanding their role in therapeutic resistance, particularly in the context of AR signaling inhibitors.

Approach:

• Literature Review: The review summarizes established and emerging evidence regarding TAMs and their influence on prostate cancer lineage plasticity, including specific pathways such as IL-6/STAT3 and TGF-beta.
• Framework Development: It discusses established myeloid programs and introduces new spatial theories related to TAMs, including emerging states like PLAC8+ TAMs and their interactions with tumor cells.

Key Findings:

• TAMs are heterogeneous and play a significant role in shaping tumor-cell fate through various mechanisms, including paracrine signaling and immune selection.
• Established myeloid programs include SPP1+/TREM2+ states and pathways such as IL-6/STAT3 and TGF-beta.
• Emerging TAM states like PLAC8+ TAMs may be associated with ARSI-induced DNPC-like remodeling.
• Single-cell and spatial transcriptomic studies reveal extensive TAM heterogeneity linked to clinical outcomes, emphasizing the need for independent validation.

Interpretation:

The review emphasizes the need to distinguish between established findings supported by multiple independent studies and emerging hypotheses regarding TAMs in prostate cancer.

Limitations:

• The proposed models require direct biochemical, genetic, and in vivo validation, particularly for emerging observations based on limited cohorts.
• Emerging observations are based on limited cohorts and need further independent validation.

Conclusion:

The review outlines a translational roadmap for TAM-directed therapy, focusing on the need for validation, functional testing, and biomarker-guided clinical testing.