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Figure 1. HER3 targeted therapies in the clinic and HER3 downstream signaling pathways. At present, the treatment strategies targeting HER3 in clinical trials mainly include monoclonal antibodies, bispecific antibodies, and antibody-drug conjugates. Among them, monoclonal antibodies are the first developed agents with the most types. Since HER3 only has weak intracellular tyrosine kinase activity, HER3 is hard to be autophosphorylated but forms dimers with other receptors, including EGFR, HER2, and IGF-1R, especially HER2, and is phosphorylated by dimerization partner through transphosphorylation. HER2/HER3 dimers can activate PI3K/AKT, JAK/STAT, and MEK/MAPK pathways, but the Src kinase pathway is predominantly mediated by the IGF-1R/HER3 dimers. In addition, Src kinase and STAT protein can upregulate PI3K expression levels. Downstream effectors in the pathways such as mTOR, STAT, and MAPK can translocate into the nucleus and control the expression of multiple genes implicated in various processes involved in cancer development, such as cancer cell proliferation, survival, migration, invasion, apoptosis, differentiation, angiogenesis, cell cycle, and drug resistance. However, when antibodies bind to HER3 monomer or heterodimer, the signaling pathway downstream of HER3 is blocked, subsequently inhibiting the cancer progression. mAbs: Monoclonal antibodies; ADCs: antibody-drug conjugates; HER: human epidermal growth factor receptor; EGFR: epidermal growth factor receptor; IGFR: insulin-like growth factor receptor 1; MAPK: mitogen-activated protein kinase; MEK: mitogen-activated extracellular signal-regulated kinase; RAF: rapidly accelerated fibrosarcoma; RAS: rat sarcoma; GTP: guanosine triphosphate; SOS: son of sevenless; GRB2: growth factor receptor-bound protein 2; P: phosphorylation; SHC: src homolog and collagen homolog; JAK: janus tyrosine kinase; STAT: signal transducers and activators of transcription; PI3K: phosphatidylinositide 3-kinases; AKT: also named PKB (protein kinase B); mTOR: mammalian target of rapamycin; PIP2: phosphatidylinositol-4,5-bisphosphate; PIP3: phosphatidylinositol-3,4,5-trisphosphate; PDK1: 3-phosphoinositide-dependent protein kinase-1; SRC: proto-oncogene tyrosine-protein kinase SRC; PTEN: phosphatase and tensin homolog.