Non-kinase Orchestrated VEGFR2–ERK Signaling is a Dependency and Pharmacological Target for Antiangiogenic Immunotherapy

Antiangiogenic immunotherapy represents a promising cancer treatment strategy. However, the efficacy of this combination approach is hindered by inadequate vascular normalization. While the fundamental role of canonical kinase-centric VEGFR-ERK signaling in angiogenesis is appreciated, the kinase-centric model overlooks non-kinase components of the pathway, such as adaptors, scaffolds, and other non-kinase interacting proteins, that could impact response to antiangiogenic therapy. Here, employing ERK kinase translocation reporter and CRISPRa screening, we revealed that the non-kinase SHC-SHCBP1 complex governed VEGFR2-ERK activity and was a dependency for aberrant tumor angiogenesis. Genetic knockout of Shcbp1 in mice sensitized tumors to VEGFR2 inhibition, preventing excessive angiogenesis, normalizing tumor vasculature, and reprogramming the immunosuppressive microenvironment to enhance immunotherapy efficacy. Mechanistically, ERK directly formed a complex with SHC and SHCBP1. Upon VEGF stimulation, active VEGFR2 recruited SHC to liberate the SHCBP1-ERK complex. SHCBP1 then triggered ERK hyperactivation by promoting ERK phosphorylation and NLS-importin-dependent nuclear shuttling, creating a feedforward loop to exacerbate pathological angiogenesis. Clinically, SHCBP1 overexpression negatively correlated with vascular normalization and antiangiogenic immunotherapy response in patients. High-throughput screening led to the development of MS1943, an inhibitor blocking SHCBP1-ERK nuclear transport. Combined with the VEGFR2 inhibitor rivoceranib and anti-PD1, MS1943 demonstrated antitumor activity against immunotherapy-resistant preclinical models, with favorable tolerance. These findings define a non-kinase-governed VEGFR2-ERK signaling pathway as a targetable dependency for tumor angiogenesis, offering the foundation for alternative antiangiogenic immunotherapy strategies.