Zeyuan Yu

Antiangiogenic immunotherapy represents a promising cancer treatment strategy. However, the efficacy of this combination approach is hindered by inadequate vascular normalization. Although the fundamental role of canonical kinase-centric VEGFR–ERK signaling in angiogenesis is appreciated, the kinase-centric model overlooks nonkinase components of the pathway, such as adapters, scaffolds, and other nonkinase interacting proteins, that could affect the response to antiangiogenic therapy. In this study, employing an ERK kinase translocation reporter and CRISPR-Pool SAM activation screening, we revealed that the nonkinase 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 nuclear localization signal-importin–dependent nuclear shuttling, creating a feedforward loop to exacerbate pathologic 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–PD-1, MS1943 demonstrated antitumor activity against immunotherapy-resistant preclinical models, with favorable tolerance. These findings define a nonkinase-governed VEGFR2–ERK signaling pathway as a targetable dependency for tumor angiogenesis, offering the foundation for alternative antiangiogenic immunotherapy strategies. Significance: The VEGFR2–ERK pathway is governed by the nonkinase SHC–SHCBP1 complex, which operates beyond the kinase-centric cascade and can be targeted to normalize tumor vessels and enhance immunotherapy efficacy.

The application of the novel KRAS^G12D inhibitor in pancreatic ductal adenocarcinoma (PDAC) is currently hindered by adaptive resistance. Metabolic reprogramming is a hallmark of KRAS^G12D signalling, yet the mechanisms linking these alterations to immunosuppression and low therapeutic response are poorly defined. To identify the key regulatory nodes connecting KRAS^G12D-driven metabolic adaptations to tumour microenvironment and develop a mechanistic-based combinatorial strategy. We integrated whole-exome sequencing, untargeted metabolomics and single-cell RNA sequencing of human PDAC specimens to analyse the metabolic-immune landscape. We evaluated therapeutic efficacy using the autochthonous mouse and patient-derived xenograft models. We found that KRAS^G12D enhanced cholesterol metabolism and promoted CD8⁺ T cell exhaustion, whereas KRAS^G12D inhibition or cholesterol synthesis blockade induced compensatory ULK1-associated autophagy. Cotargeting cholesterol metabolism and autophagy potentiated the antitumour efficacy of the KRAS^G12D inhibitor MRTX1133 and alleviated CD8⁺ T cell exhaustion. Mechanistically, KRAS^G12D transcriptionally upregulated USP20 via EGR1, which simultaneously deubiquitinated and stabilised 3-hydroxy-3-methylglutaryl-CoA reductase and ULK1, thereby orchestrating cholesterol metabolism and autophagy-associated survival. Genetic depletion or pharmacological inhibition of USP20 with GSK2643943A suppressed these pathways and restored CD8⁺ T cell function, improving responses to MRTX1133 and anti-programmed cell death protein-1 (anti-PD-1). In preclinical PDAC models, triple therapy with GSK2643943A, MRTX1133 and anti-PD-1 elicited a robust therapeutic response and induced significant tumour regression. USP20 acts as a critical metabolic checkpoint that orchestrates CD8⁺ T cell exhaustion and therapeutic response. Targeting the USP20-cholesterol-autophagy axis represents a promising strategy to reverse immune suppression and unlock the full potential of KRAS^G12D inhibitors in PDAC.

Supplementary Figures and Tables

Primary cilia detect and transmit environmental signals into cells. Primary cilia are absent in a subset of ductal carcinomas characterized by distinctive biological activities, and recovery of cilia with normal functionality has been shown to have therapeutic potential in some cancer types. Therefore, elucidation of the underlying mechanism and clinical significance of ciliary loss in ductal carcinomas could help develop effective treatment strategies. Here, we identified a link between Shc1-binding protein (SHCBP1) and cilia in ductal carcinomas. Shcbp1 knockout in transgenic mice profoundly impeded tumor progression and metastasis, prolonging survival. Single-cell transcriptome analysis revealed a functional connection between SHCBP1 deficiency and increased tumor ciliogenesis. SHCBP1 ablation restored ciliogenesis in unciliated ductal carcinoma by promoting the proximity between the midbody remnant (MBR) and centrosome through enhanced Rab8 GTPase activity and Rab8GTP positioning within the MBR. Inhibition of tumor progression by SHCBP1 loss relied on the recovery of ciliogenesis. Analysis of a large cohort of patients with ductal carcinoma revealed a negative correlation between SHCBP1-induced ciliary loss and patient prognosis. Restoring ciliogenesis via SHCBP1 ablation elicited therapeutic effects in patient-derived xenograft models. Together, this study delineates that induction of MBR-centrosome proximity through SHCBP1-deficiency reactivates ciliogenesis, offering unique opportunities for the treatment of unciliated ductal carcinomas.Significance:SHCBP1 depletion rescues tumor ciliogenesis by enhancing Rab8 GTPase activity to restore the proximity of the midbody remnant to the centrosome, which impedes progression of ductal carcinomas and suggests potential therapeutic strategies.

Although glycolysis is a metabolic hallmark of pancreatic ductal adenocarcinoma (PDAC), it remains unclear whether the excessive lactate produced regulates CAF lactylation to promote extracellular matrix (ECM) deposition. The multi‐omics and spontaneous model findings indicate that lactate accumulation in the tumor microenvironment (TME) promotes histone H3 lysine 18 lactylation (H3K18la) and activation of cancer‐associated fibroblasts (CAFs), leading to both ECM densification and impaired immunotherapy efficacy in PDAC. Mechanistically, ubiquitin‐conjugating enzyme E2T (UBE2T) acts as an initiating factor that promotes p53 positive feedback degradation through modulation of ribosome biogenesis, thereby enhancing lactate metabolic crosstalk via glycolytic reprogramming. Genetic ablation or pharmacological inhibition of UBE2T using the selective inhibitor pentagalloylglucose (PGG) disrupts lactate metabolic crosstalk, suppresses stromal deposition, and promotes intratumoral CD8 ⁺ T cells infiltration. Furthermore, the combination of PGG and anti‐PD‐1 therapy exhibits synergistic effects and survival benefits in spontaneous PDAC mice and immune‐reconstituted patient‐derived xenografts. Collectively, these findings reveal that UBE2T drives p53 positive feedback degradation to enhance glycolysis of PDAC, leading to excessive lactate production, which promotes H3K18la in CAFs and subsequent ECM deposition. Targeting UBE2T represents a potential strategy to improve the efficacy of immunotherapy in PDAC.

USP20 deletion suppresses PDAC progression

GSK2643943A enhances cadonilimab efficacy in PDXs

Inflammation promotes ECM-like characteristics of malignant cells and communication with CAFs

Simvastatin suppresses PDAC progression

CP organoids exhibit more proliferation ability, ECM-like characteristics and activation of inflammatory signaling