Naturally Occurring Feline Cancers in Comparative Oncology: Translational Insights from Oral Squamous Cell Carcinoma and Mammary Carcinoma

Background: Comparative oncology uses naturally occurring cancers in companion animals to study tumor biology and therapeutic responses relevant to human cancer. Spontaneous feline tumors are increasingly recognized as useful comparative models because they arise in immunocompetent hosts, develop under shared environmental exposures, and can reproduce selected clinical, histopathologic, molecular, and therapeutic features of human malignancies. Methods: This review compares feline oral squamous cell carcinoma (FOSCC) with human head and neck squamous cell carcinoma (HNSCC), and feline mammary carcinoma (FMC) with human breast cancer, emphasizing shared pathologic, molecular, tumor microenvironment, and therapeutic features. Results: Recent immunohistochemical, genomic, transcriptomic, and biomarker studies have identified shared features between feline and human cancers. FOSCC resembles human HNSCC through aggressive local invasion, histologic features, therapeutic resistance, and recurrent alterations of TP53, MYC, and PTEN. FMC shows strong overlap with aggressive human triple-negative breast cancer, including reduced hormone receptor expression, recurrent TP53, PIK3CA, and CXCL12/CXCR4 signaling alterations, and tumor microenvironment features involving immune-checkpoint, inflammatory, and angiogenic pathways. FOSCC clinical trials and emerging clinical investigations into FMC treatments further support the use of cats for translational therapy evaluation. Conclusions: FOSCC and FMC are promising comparative oncology models for human HNSCC and aggressive breast cancer, respectively. Future multicenter studies incorporating standardized tumor classification and grading, predefined stratification criteria, and clinically meaningful endpoints will be essential to strengthen their translational value.