Orphan nuclear receptor 4A1 (NR4A1, Nur77) plays a crucial role in regulating immune cell metabolism and function within the tumor microenvironment (TME), thus influencing cancer progression and serving as a potential therapeutic target for cancer immunotherapy. A comprehensive review discussing the multifaceted roles of NR4A1 in immune cells and the exploitation of that knowledge for therapeutic development is lacking in the field. This review explores diverse functions of NR4A1 in tumor-associated immune cells, including T cells, monocytes, natural killer cells, B cells, dendritic cells, macrophages, and neutrophils. NR4A1 contributes to immune regulation by impacting cytokine production, cell differentiation, and immune cell exhaustion. We highlight how NR4A1 in immune cells within the TME may be either a positive (e.g., macrophages in colon cancer) or negative prognostic factor (e.g., T cells in melanoma), depending on the cancer and immune cell context. Additionally, this review also highlights potential therapeutic strategies targeting NR4A1, leading to its inhibition, activation, or degradation to restore immune cell function and enhance anti-tumor immunity. Such therapies could potentially improve patient outcomes by altering immune cell behaviors, blocking intrinsic tumor growth pathways, or via both mechanisms. However, the development of NR4A1-targeted therapies will be dependent on further research to better understand lineage-specific roles of NR4A1 and the underlying mechanisms across different cancer types and immune cells.

Renal cell carcinoma (RCC), particularly the clear cell subtype, is a solid tumor characterized by a high degree of immune cell infiltration, progressive immune dysfunction, and favorable response to immune checkpoint inhibitors (ICIs). Dual checkpoint inhibition or single-agent ICIs with anti-angiogenic therapies have become the standard of care in the treatment of advanced and metastatic RCCs. Locally advanced and oligometastatic RCCs are distinct clinical categories that are characterized by local invasion and initially limited metastatic spread, respectively, with different therapeutic responses and prognoses compared to either localized or advanced diseases. Herein, we summarize the biology, treatment, and molecular profiling of RCCs, providing an update on the clinical trials pertaining to cancer patients with locally advanced and oligometastatic RCC. We also discuss molecular features that could contribute to a better understanding of the tumor biology driving locally advanced and oligometastatic RCC.