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Protein-based pan-RAS inhibitor induces tumor regression in female mice via IFNγ and CD8+ T cell-dependent tumor necrosis
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Protein-based pan-RAS inhibitor induces tumor regression in female mice via IFNγ and CD8+ T cell-dependent tumor necrosis
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Journal Article
Protein-based pan-RAS inhibitor induces tumor regression in female mice via IFNγ and CD8+ T cell-dependent tumor necrosis
2026
Overview
Mutations in K/H/N-RAS occur in approximately 30% of human cancers, yet most RAS mutants remain undruggable in clinical settings. Here, we describe a protein-based pan-RAS inhibitor, RRSP-RBD, that combines a RAS/Rap1A-specific endopeptidase (RRSP) with a RAS-binding domain (RBD). This engineered fusion protein localizes to RAS on the plasma membrane, where it cleaves RAS, disrupts RAS-effector interactions, and effectively inhibits downstream RAS signaling. To achieve intracellular delivery of RRSP-RBD in vivo, we engineer two cell-permeable variants. The diphtheria toxin-based version (RRSP-RBD-DTB) demonstrates femtomolar anti-tumor potency and induces tumor regression in a xenograft mouse model. The cell-permeable peptide-based version (RRSP-RBD-TAT) exhibits robust anti-tumor activity in syngeneic models without inducing irreversible toxicity in normal tissues. Interestingly, anti-tumor efficacy of RRSP-RBD-TAT critically depends on the tumor microenvironment, requiring infiltration by IFNγ
+
CD8
+
T cells to mediate tumor regression. Pharmacokinetic and toxicity evaluations indicate that RRSP-RBD is tolerated under the conditions tested and support further investigation as a protein-based pan-RAS inhibitor (all mouse studies were performed in female mice).
Many cancers depend on RAS signaling, but blocking diverse RAS mutants remains challenging. Here, authors engineer a protein-based pan-RAS inhibitor that induces tumor regression in mouse models and reveals an immune-dependent mechanism of action
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
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/ 13/51
/ 13/95
/ 14/19
/ 14/34
/ 14/63
/ 38/61
/ 631/45
/ 631/57
/ 64/60
/ 82/80
/ 82/83
/ Animals
/ Antineoplastic Agents - pharmacology
/ Cancer
/ CD8-Positive T-Lymphocytes - drug effects
/ CD8-Positive T-Lymphocytes - immunology
/ CD8-Positive T-Lymphocytes - metabolism
/ Cells
/ Enzymes
/ Female
/ Females
/ Humanities and Social Sciences
/ Humans
/ Interferon-gamma - immunology
/ Interferon-gamma - metabolism
/ Mice
/ Mutants
/ Mutation
/ Necrosis
/ Peptides
/ Proteins
/ ras Proteins - antagonists & inhibitors
/ Recombinant Fusion Proteins - genetics
/ Recombinant Fusion Proteins - pharmacology
/ Science
/ Signal Transduction - drug effects
/ Toxicity
/ Toxins
/ Tumors
