S100A4 oncoprotein plays a critical role during prostate cancer progression and induces immunosuppression in host tissues. We hypothesized that S100A4-regulated oncogenic activity in immunosuppressed prostate tumors promotes growth of neoplastic cells, which are likely to become aggressive. In the current study, we investigated whether biopsy-S100A4 gene alteration independently predicts the outcome of disease in patients and circulatory-S100A4 is druggable target for treating immunosuppressive prostate cancer. Aided by DECIPHER-genomic test, we show biopsy-S100A4 overexpression as predictive of (i) poor ADT response and (ii) high risk of mortality in 228 radical prostatectomy-treated patients. Furthermore, analysis of tumor genome data of more than 1,000 patients with prostate cancer (PRAD/SU2C/FHCRC studies) validated the association of S100A4-alteration to poor survival and metastasis. We show that increased serum-S100A4 levels are associated to the prostate cancer progression in patients. The prerequisite for metastasis is the escape of tumor cells via vascular system. We show that extracellular-S100A4 protein as a growth factor induces vascular transmigration of prostate cancer cells and bone demineralization thus forms an ideal target for therapies for treating prostate cancer. By employing surface plasmon resonance and isothermal titration calorimetry, we show that mab6B12 antibody interacts with and neutralizes S100A4 protein. When tested for therapeutic efficacy, the mab6B12 therapy reduced the (i) osteoblastic demineralization of bone-derived MSCs, (ii) S100A4-target (NFκB/MMP9/VEGF) levels in prostate cancer cells, and (iii) tumor growth in a TRAMPC2 syngeneic mouse model. The immuno-profile analysis showed that mAb6B12-therapy (i) shifted Th1/Th2 balance (increased Stat4+/T-bet+ and decreased GATA2+/CD68+/CD45+/CD206+ cells); (ii) modulated cytokine levels in CD4+ T cells; and (iii) decreased levels of IL5/6/12/13, sTNFR1, and serum-RANTES. We suggest that S100A4-antibody therapy has clinical applicability in treating immunosuppressive prostate cancer in patients.

Prostate cancer (CaP) is the most diagnosed cancer in males and the second leading cause of cancer deaths. Patients with localized tumors are generally curable. However, no curative treatment exists for patients with advanced and metastatic disease. Therefore, identifying critical proteins involved in the metastatic process would help to develop new therapeutic options for patients with advanced and aggressive CaP. We provide strong evidence that Myeloid differentiation factor-2 (MD2) plays a critical role in metastasis and CaP progression. Analysis of tumor genomic data showed that amplifications of MD2 and increased expression are associated with poor outcomes in patients. Immunohistochemistry analysis of tumor tissues showed a correlation between the expression of MD2 and cancer progression. The Decipher-genomic test validated the potential of MD2 in predicting metastasis. In vitro studies demonstrated that MD2 confers invasiveness by activating MAPK and NF-kB signaling pathways and inducing epithelial–mesenchymal transition. Furthermore, we show that metastatic cells release MD2 (sMD2). We measured serum-sMD2 in patients and found that the level is correlated to disease extent. We determined the significance of MD2 in metastasis in vivo and as a therapeutic target, showing that the molecular and pharmacological targeting of MD2 significantly inhibited metastasis in murine models. We conclude that MD2 predicts metastatic behavior, and serum-MD2 could be studied as a potential non-invasive biomarker for metastasis, whereas MD2 presence on prostate biopsy predicts adverse disease outcome. We suggest MD2-targeted therapies could be developed as potential treatments for aggressive metastatic disease.

Melanoma is one of the most aggressive skin cancers, with increasing rates of occurrence. Although it has not traditionally been considered hormonally driven, recent evidence links androgen receptor (AR) signaling to important aspects of melanoma biology, including tumor growth, metastasis, immune evasion, and resistance to therapy. Mechanistically, AR promotes melanoma progression by activating a pro-metastatic gene program, suppressing anti-tumor immune responses, and altering the tumor microenvironment. Additionally, emerging data indicate AR’s involvement in resistance to chemotherapy and immune-based therapies. This review provides a comprehensive overview of AR’s intricate role in melanoma, focusing on its molecular mechanisms, its impact on immune evasion and therapy resistance, and its potential clinical applications. We also assess AR-targeted strategies, including androgen deprivation therapy and AR antagonists, to improve the effectiveness of chemotherapy, targeted therapy, and immunotherapy. Understanding AR’s role in melanoma could lead to new treatment options, particularly for sex-specific patient groups.

Melanoma is one of the most aggressive skin cancers, with increasing rates of occurrence. Although it has not traditionally been considered hormonally driven, recent evidence links androgen receptor (AR) signaling to important aspects of melanoma biology, including tumor growth, metastasis, immune evasion, and resistance to therapy. Mechanistically, AR promotes melanoma progression by activating a pro-metastatic gene program, suppressing anti-tumor immune responses, and altering the tumor microenvironment. Additionally, emerging data indicate AR's involvement in resistance to chemotherapy and immune-based therapies. This review provides a comprehensive overview of AR's intricate role in melanoma, focusing on its molecular mechanisms, its impact on immune evasion and therapy resistance, and its potential clinical applications. We also assess AR-targeted strategies, including androgen deprivation therapy and AR antagonists, to improve the effectiveness of chemotherapy, targeted therapy, and immunotherapy. Understanding AR’s role in melanoma could lead to new treatment options, particularly for sex-specific patient groups.

PTPN6 encodes SHP-1, a central regulator of immune tolerance and a critical signaling brake across innate and adaptive immunity in autoimmune disease. Predominantly expressed in hematopoietic cells, SHP-1 restrains receptor-proximal signaling downstream of antigen, cytokine, and pattern-recognition receptors, thereby setting activation thresholds that preserve immune homeostasis and limit autoreactivity. Converging evidence from human genetics, patient-derived immune cells, and animal models indicates that diminished SHP-1 activity promotes persistent autoreactive lymphocyte responses, exaggerated inflammatory signaling, and tissue-specific injury across systemic lupus erythematosus, rheumatoid arthritis, neutrophilic dermatoses, multiple sclerosis, psoriasis, and type 1 diabetes. Beyond its role in disease pathogenesis, SHP-1 has emerged as a therapeutically relevant node, particularly through strategies designed to enhance phosphatase activity and restore immune restraint. However, clinical translation remains constrained by challenges in phosphatase selectivity, context-dependent biology, and tissue-specific delivery. This review integrates current understanding of SHP-1 regulatory mechanisms, disease-specific evidence, and emerging translational opportunities, highlighting PTPN6 /SHP-1 as a candidate target for precision immunomodulation in autoimmune disease.

The role of regional lymph nodes in melanoma metastasis has long been recognized. This review will detail the evolving role of sentinel lymph node biopsy (SLNB) in melanoma management in the era of adjuvant therapies. We analyze key themes and findings from recent publications, highlighting both areas of consensus and ongoing controversies. While the landscape of melanoma management continues to evolve with the advent of novel therapeutic combinations, SLNB remains a valuable tool for staging and potentially provides therapeutic benefit. However, optimal patient selection for SLNB requires careful consideration of individual risk factors and benefits of adjuvant therapy.