Breast cancer (BC) metastasis remains a major cause of mortality, yet the molecular mechanisms driving this process are incompletely understood. This study identifies TMEM216, a transmembrane protein implicated in ciliary homeostasis, as a suppressor of lung metastasis in BC. Using mammary-specific Tmem216 knockout mice, we demonstrate that Tmem216 deficiency promotes lung metastasis without affecting primary tumor proliferation. Clinical analyses reveal reduced TMEM216 expression in metastatic lesions and aggressive cell lines, correlating with poor patient distant metastasis-free survival. Mechanistically, TMEM216 interacts with IGF1R and binds to IRS4 via the conserved K79-D1049 interaction, disrupting the IGF1R-IRS4 complex formation and suppressing IGF pathway activation. Rescue experiments in vitro and in vivo confirm that TMEM216-mediated metastasis inhibition depends on IGF signaling modulation. Tissue microarray analyses further establish an inverse correlation between TMEM216

Tian, Nikan, and colleagues report Clone F-Hprt, an IGF1R-targeted antibody–siRNA conjugate designed to expand oligonucleotide delivery beyond the liver. Local and systemic administration produced Hprt knockdown in CNS and selected peripheral tissues, supporting IGF1R as a complementary BBB shuttle receptor.

Background/aims To explore the roles of insulin-like growth factor 1 receptor (IGF1R) and thyroid-stimulating hormone receptor (TSHR) in extraocular muscle pathology.Methods Extraocular muscle specimens were obtained during rectus muscle myectomy surgeries performed for large-angle strabismus correction in patients with thyroid-associated orbitopathy (TAO) and during rectus muscle resection surgeries performed for congenital strabismus in normal controls. Immunohistochemistry was employed to detect and compare between-group IGF1R and TSHR expression; ImageJ software was used to assess the staining area and H&E staining was used to evaluate morphological differences in tissues. Intergroup comparisons were conducted using the Mann-Whitney U test.Results Histological examination of the extraocular muscle specimens revealed greater fibrosis in the TAO group (n=12) than in the control group (n=6). Immunohistochemistry (IHC) revealed significantly higher expression of both IGF1R and TSHR in the TAO group, particularly in elongated fibroblast-like cells and some myocytes, than in the control group, which exhibited minimal expression. Semiquantitative analysis confirmed significantly larger mean expression areas for IGF1R and TSHR in the TAO group than in the control group (p

Oncolytic herpes simplex virus 1 (oHSV) is a promising viro-immunotherapy that directly lyses tumor cells while reshaping the tumor microenvironment (TME) and stimulates anti-tumor immunity. However, despite encouraging preclinical and clinical activity, treatment-induced adaptations in tumor cells and the surrounding microenvironment can promote survival, repair, repopulation, immune escape, and recurrence, thereby limiting durable therapeutic benefit. In our recent article published in Cell Death & Disease,1 we asked why oHSV often fails to achieve durable tumor control and whether the adaptive resistance it induces can be therapeutically overcome.

FDA-approved oncolytic herpes simplex virus-1 (oHSV) therapy has emerged as a promising viro-immunotherapy for solid tumors. However, tumor- and tumor microenvironment (TME)-associated adaptations following viral treatment, such as feedback immune suppression, neoangiogenesis, and enhanced tumor aggressiveness, often hinder complete tumor eradication. A deeper understanding of the molecular mechanisms underlying resistance to oHSV is crucial to enhancing its clinical impact. We recently discovered that oHSV induces Insulin-like growth factor 2 (IGF2) secretion, shaping an immunosuppressive TME. Similarly, radiotherapy (RTx) activates the IGF1/IGF1R and YAP1 signaling pathways, further promoting therapeutic resistance. In this study, we investigated how oHSV-induced Insulin-like growth factor 1 receptor (IGF1R) signaling drives feedback pro-survival and proliferative pathways in tumor cells and evaluated the therapeutic potential of combining IGF1R blockade with oHSV and RTx. We first demonstrated that oHSV activates IGF1R signaling in vitro and in vivo, promoting tumor proliferation. While IGF1R-targeted monotherapies have shown limited cytotoxicity, its combination with oHSV led to a modest but significant increase in cytotoxicity across tested breast cancer (BC) and primary glioblastoma (GBM) cells in vitro and in vivo xenograft models. Furthermore, we observed that co-treatment with oHSV and RTx robustly activated both IGF1R and YAP1 in resistant cells, revealing the IGF1R/YAP1 axis as a key mediator of resistance to dual oHSV and RTx therapy. Notably, the triple combination of oHSV, RTx, and IGF1R blockade yielded synergistic anti-tumor effects, abolished YAP1 expression and nuclear localization, and significantly enhanced survival in orthotopic BC and GBM models. Collectively, these findings identify the IGF1R/YAP1 axis as a critical driver of resistance to oHSV and RTx and provide a strong rationale for the clinical evaluation of this triple-combination strategy to enhance therapeutic efficacy in patients with BC and GBM.

A blood-brain barrier-like vascular gate in small cell lung cancer and other neuroendocrine cancers blocks immune cells and drives resistance to immunotherapy. Targeting the proteins IGF1R or IGFBP5 b...

RSV is the leading cause of infant hospitalizations and a significant cause of paediatric and geriatric morbidity worldwide. Recently, we reported that insulin-like growth factor 1 receptor (IGF1R) wa...

IntroductionThe insulin-like growth factor (IGF-1/IGF1R) pathway has been implicated in breast cancer aggressiveness; however, inhibition of this pathway has...