Abstract Oncogenic RAS mutations are among the most prevalent and intractable drivers of human cancer, present in nearly 20% of cases. These mutations not only fuel uncontrolled tumor growth but also reprogram cellular metabolism by dramatically increasing macropinocytosis. This unique “nutrient scavenging” pathway is critical for RAS-driven cancer cells yet largely dispensable in normal tissues and presents a powerful and underexploited therapeutic opportunity. To address this unmet need, we developed CQ-0736, a first-in-class “Trojan horse” therapeutic that exploits macropinocytosis to selectively co-deliver two synergistic drugs into the pan-KRAS tumors. CQ-0736 is a polysaccharide-based dual-drug conjugate consisting of a 100 kDa dextran backbone covalently grafted with docetaxel (DTX) and gamma-linolenic acid (GLA). This drug construct converts the RAS-driven tumor cell membrane from a “natural barrier” into an “active transport interface”, enabling unprecedented levels of intracellular drug accumulation specifically at tumor sites.Preclinical studies demonstrate the highly transformative potential of CQ-0736. In vitro, it exhibited markedly greater cytotoxicity than parent DTX across multiple pan-KRAS cancer cell lines harboring KRASG12D, KRASG12C, and KRASWT mutations. Several in vivo xenograft models showed that CQ-0736 achieved more than 95% tumor growth inhibition without weight loss or observed toxicity, regardless of KRAS mutation status. Remarkably, the direct head to head in vivo comparisons revealed that CQ-0736 significantly outperformed the word class pan-RAS inhibitor RMC-6236 and the marketed KRAS targeted drug Krazati, displaying superior efficacy, longer durability, and much less drug resistance.Mechanistic analyses confirmed that CQ-0736 robustly suppresses proliferation (decreasing PCNA and Ki-67) while driving apoptosis (elevating cleaved PARP), producing superior effects to parent DTX. These findings underscore the conjugate’s dual impact on tumor biology and highlight its potential to overcome key limitations of both conventional chemotherapy and next-generation targeted RAS inhibitors, including systemic toxicity and acquired resistance. Conclusion: CQ-0736 represents a highly innovative and clinically promising therapeutic strategy for RAS-driven cancers, a disease with devastating prognosis and few effective options. By turning a fundamental vulnerability of RAS-driven tumors into a drug delivery advantage, CQ-0736 opens a new therapeutic paradigm with the potential to significantly improve outcomes for patients with some of the most aggressive and treatment-resistant malignancies. Citation Format: Jinghua Hu, Si Wang, Yikang Shi, Xiaohai Li, Weiping Jia, Maoxu Ge, Tingchao Liu, Li Yang, Meng Huo, Anny Wang, Ling Zhao, . CQ-0736, a new polysaccharide-based therapeutic modality, targets pan-KRAS tumors with robust antitumor activity via macropinocytosis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6731.
Hu et al. (Fri,) studied this question.