Advancements in Sex-Specific Tumor Heterogeneity

Prem Prakash Kushwaha^1*SWATI KUSHWAHA²Radha Kushwaha^2*

• ¹Cleveland State University, Cleveland, Ohio, United States
• ²Allahabad University, Allahabad(Prayagraj), Uttar Pradesh, India

Sex differences play a fundamental role in cancer incidence, progression, and treatment response, yet their influence remains underexplored in many aspects of oncology. Emerging research suggests that biological factors such as sex hormones, genetic variations, immune system differences, and metabolic pathways contribute to distinct tumor behaviors and therapeutic outcomes between males and females. Understanding these disparities is critical for advancing precision medicine and improving patient care. This special issue, Advancements in the Heterogeneity of Sex for Tumors, brings together ten cutting-edge studies that investigate the impact of sex on cancer biology across a range of malignancies. These investigations examine molecular mechanisms, prognostic markers, and therapeutic targets, revealing how sex affects tumor initiation, progression, immune responses, and treatment resistance, paving the way for personalized therapies.The first review published by Zhu and Zhao (2024), their review explores the influence of sex on bladder cancer, from incidence to biology and outcomes. They asses risk factors like smoking, occupational exposures, and genetic mutations, alongside sex-based differences in cancer development. They provide comprehensive insights into the roles of hormones, chromosomes, metabolism, and the microbiome, while also highlighting gender gaps in diagnosis and prognosis. Their work underscores the need for more research and sex-specific treatments to improve care for all patients. Li et al. (2024) analyze cutaneous melanoma using TCGA and GEO data, integrating mutation, clinical, and single-cell sequencing to identify key genes. They developed a prognostic model using LASSO, linking genes to immune responses through functional and immunological analyses. They showed GMR6's role in melanoma cell proliferation, invasion, and migration. These findings identify potential therapeutic targets, offering new avenues to improve patient outcomes in cutaneous melanoma, particularly through targeting GMR6-mediated mechanisms.A mini review published by Su et al., 2024 explores gender differences in hepatocellular carcinoma, emphasizing on sex hormones, genetics, and environmental factors. They highlight the liver's sexual dimorphism and gender-specific risks like alcohol and obesity in cancer development. The review explores molecular mechanisms, including androgen and estrogen signaling, influencing tumor biology; and highlighting the need for genderspecific research to improve diagnostics, treatment precision, and personalized therapies, aiming to enhance outcomes for liver cancer patients. 2024) investigate AIB1's role in endometrial cancer, focusing on its impact on aerobic glycolysis and tumor progression. AIB1 is linked to poor prognosis and identified as a potential therapeutic target. Using cell lines and mouse models, researchers confirmed AIB1's high expression and its role in tumor proliferation and invasion. Mechanistically, AIB1 is acetylated by PCAF, binds to c-myc, and regulates glycolysisrelated genes. These findings suggest targeting AIB1-mediated glycolysis could offer a novel strategy for treating estrogen-dependent endometrial cancer, advancing personalized therapies.In another study Xia et al., 2024 investigated the chromatin accessibility in peripheral blood mononuclear cells (PBMCs) of breast cancer patients to assess its diagnostic and prognostic potential. Using ATAC sequencing and bioinformatics analysis, they identified 1,906 differentially accessible regions and 1,632 differentially expressed genes. Nine key genes (e.g., JUN, CDC42, TRIB1) and five transcription factors (NFY, Sp2, ELK1) were linked to breast cancer progression. The findings suggest chromatin accessibility in PBMCs as a promising biomarker for early detection and therapeutic innovation in breast cancer. 2024) investigate BYL-719, a PI3K p110α inhibitor, for targeting breast cancer stem cells (BCSCs) and overcoming drug resistance. Using a 3D mammosphere model, they found BYL-719 inhibits BCSC proliferation, stemness, and epithelial-tomesenchymal transition (EMT). The drug suppresses key pathways like PI3K/AKT/mTOR, Notch, JAK-STAT, and MAPK/ERK, which regulate tumor microenvironment dynamics. They demonstrated that BYL-719 overcomes resistance in eribulin-resistant breast cancer cells. These results suggest combining BYL-719 with other therapies could enhance breast cancer treatment strategies. 2024) explore cell communication in hepatocellular carcinoma (HCC) using single-cell sequencing and clustering analysis. They identified malignant and cancerassociated fibroblast subpopulations, emphasizing SPP1-mediated interactions. Two clusters, C1 and C2, were distinguished, with C1 showing higher cytotoxicity and invasion. A gene risk model revealed increased immune pathway activity in C1, while high-risk scores correlated with poorer prognosis. They showed that ABCA1 promotes HCC progression by enhancing proliferation, invasion, and migration while reducing apoptosis. These findings provide critical insights into HCC pathogenesis and prognosis.Hong et al. ( 2025) investigated WNT signaling genes in melanoma, identifying 19 prognostic-related genes and developing a 13-gene model using LASSO regression. Key findings linked CSNK1E and RAC3 to epithelial-to-mesenchymal transition and immune evasion. They identified role of CSNK1E in melanoma progression via the TGF-β pathway. These results suggest targeting CSNK1E and WNT/TGF-β pathways could enhance melanoma treatment and address therapy resistance. Wang et al. (2025) investigated inflammatory gene expression in epithelial ovarian cancer and its role in immunotherapy resistance. Transcriptome analysis revealed two inflammatory gene patterns, differing in immune infiltration, prognosis, and treatment response. The high-risk group showed elevated M2 macrophage infiltration, increased tumor stemness, poorer prognosis, and reduced sensitivity to chemotherapy and immune checkpoint inhibitors. These findings underscore inflammation-related genes as potential targets for enhancing immunotherapy and prognostic evaluation, offering new strategies for early intervention and patient management.Zhang and Pang (2025), studied cell senescence-associated genes in thyroid cancer, developing a prognostic model using differential expression, Cox regression, and LASSO analyses. Validated with Kaplan-Meier and ROC curves, the model predicts patient survival, tumor mutation burden, and immunotherapy response across risk groups. Their findings offer new insights into thyroid cancer progression and immunotherapy, highlighting potential pathways for personalized treatment strategies.These studies collectively advance our understanding of cancer biology by uncovering sex-based differences, molecular mechanisms, and therapeutic targets, paving the way for personalized treatments and improved patient outcomes across various malignancies.