NMS-873

The formulation co-delivered NMS-873 (NM), a VCP/p97 inhibitor, to induce endoplasmic reticulum stress (ERS) and proteostasis collapse, together with bispecific PD-L1/CTLA-4 aptamers (P1C4) for dual checkpoint blockade. A complementary SLN formulation encapsulating galunisertib (G) and DNase (DN) degraded neutrophil extracellular traps (NETs) and suppressed tumor-associated neutrophils (TANs), thereby reshaping the immunosuppressive TME...In vivo PET/MRI imaging and immunohistopathological analyses confirmed selective tumor accumulation and effective tumor regression. This peptide-guided, TME-tailored SLN strategy achieves coordinated immune reprogramming, ERS induction, EMT/CSC reversal, NET disruption, and dual checkpoint blockade, offering a clinically translatable platform to overcome chemoimmunotherapy resistance in EGFR/PD-L1/CTLA-4-driven CRC.

VCP drives NED in PCa cells through a complex interplay involving the Pim1 axis and autophagy pathways. These findings highlight the potential of targeting VCP/p97 and its associated mechanisms as therapeutic strategies to inhibit NED progression.

We aimed to investigate the efficacy of endoplasmic reticulum (ER)-associated protein degradation (ERAD) inhibitors (EerI and NMS-873) in enhancing radiation-induced ICD in esophageal cancer (EC)...ICD hallmark genes, especially CALR, are correlated to immune cell infiltration and clinical outcomes in EC. The present results demonstrated an important method to improve the immunogenicity of EC cells for enhanced antitumor immune response.

Western blot analysis validated the degradation of cyclin D1 and Securin, which depends on proteasome but not on p97. Differing regulation of cell cycle proteins by p97 and the proteasome may, therefore, explain the therapeutic efficacy of p97 inhibitors in colon cancer.