# TREM2 in Urological Malignancies and Benign Lesions: Mechanistic Convergence, Functional Heterogeneity, and Translational Perspectives: A Narrative Review

## TL;DR

This review explores how TREM2 behaves differently in urological cancers and benign conditions, offering insights into its role in disease progression and potential for treatment.

## Contribution

The first systematic synthesis of TREM2's role in urological malignancies and benign conditions, revealing a common signaling mechanism in cancers.

## Key findings

- TREM2 upregulation correlates with poor outcomes in urological cancers.
- TREM2 promotes tumor growth via the PI3K/AKT pathway in urological malignancies.
- TREM2 may protect against non-malignant kidney injury and is detectable in urine for disease monitoring.

## Abstract

Urinary system cancers, including bladder, prostate, and kidney cancers, impose a substantial global health burden. Although immunotherapy benefits certain patients, many ultimately develop resistance to these drugs. This review examines the role of the TREM2 protein in these diseases. TREM2 functions as a double-edged sword. In urinary system cancers, it generally promotes tumor growth and suppresses anti-tumor immunity through a common mechanism involving the PI3K/AKT pathway. Conversely, in cases of benign kidney injury, it may exert a protective effect. Additionally, TREM2 is detectable in urine, presenting a potential noninvasive method for disease surveillance. Clarifying this dual role could facilitate the development of combined strategies involving immunotherapy and targeted drugs, ultimately improving patient survival.

Triggering receptor expressed on myeloid cells-2 (TREM2) is a key myeloid immune checkpoint for macrophage plasticity. However, its functional landscape in urology is still incomplete. This review addresses this gap by providing the first systematic synthesis of TREM2 in urological malignancies (bladder, prostate, and renal cell carcinomas) and benign conditions. We find a strong correlation between TREM2 upregulation and adverse clinical outcomes in these cancers. Importantly, we highlight the phenomenon of “mechanistic convergence”: unlike the high context-dependency of other organ systems, TREM2 appears to drive progression in urological malignancies by a common convergent signaling hub, the PI3K/AKT pathway. This contrasts sharply with its metabolic role in benign prostatic hyperplasia and its protective role in non-malignant renal injury. We also consider the translational potential of TREM2 as a prognostic biomarker (specifically urine detection) and as a therapeutic target to reverse immunotherapy resistance.