How Nerofe+ldDox Reprograms the Immune Microenvironment in KRAS-Mutant Tumors | Oncotarget

Описание: Oncotarget #published this #research paper on December 24, 2025, in Volume 16, entitled “Nerofe+ldDox releases c-Jun from nuclear ST2 to reprogram the immune microenvironment in mtKRAS tumors" by #researchers from Immune System Key (ISK) Ltd., Jerusalem 9746009, Israel; Department of Bio-Informatics, Lev Academic Center (JCT), Jerusalem 91160, Israel; Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
#cancer #KRAS #tumor #microenvironment #oncology #paperspotlight #openaccess #openscience #peerreview #journal #publishing #meded

DOI - https://doi.org/10.18632/oncotarget.2...

Correspondence to - Yoram Devary - [email protected]

Abstract

Background/Objectives: Mutant KRAS (mtKRAS) tumors are highly immunosuppressive, largely through secretion of IL-10 and TGF-β2, which prevent immune cell infiltration. Nerofe (dTCApFs), a peptide derivative of Tumor Cell Apoptosis Factor, induces endoplasmic reticulum stress and modulates immune signaling through the T1/ST2 receptor, which is overexpressed in mtKRAS tumors. We evaluated whether combining Nerofe with low-dose doxorubicin (ldDox) could remodel the immune microenvironment and overcome tumor immunosuppression.

Methods: In vitro experiments were performed in PANC-1 pancreatic adenocarcinoma cells harboring a KRAS mutation. Cytokine expression, c-Jun activity, and c-Jun–ST2 binding were measured by western blotting, immunocytochemistry, and immunoprecipitation. In a clinical trial (NCT05661201), patients with mtKRAS tumors received weekly Nerofe (288 mg/m²) plus ldDox (8 mg/m²). Tumor biopsies were analyzed by immunohistochemistry before treatment and after 7 weeks.

Results: Nerofe+ldDox treatment increased IL-2 and suppressed IL-10 in PANC-1 cells, reversing the immunosuppressive cytokine profile. Patient biopsies confirmed these effects, showing higher IL-2, lower IL-10, and increased infiltration of NK cells, CD8+ cytotoxic T lymphocytes, and CD4+ helper T cells. KRAS protein levels were reduced in post-treatment biopsies. Mechanistically, Nerofe+ldDox elevated total c-Jun protein but reduced phosphorylation at Ser63 and Ser73. Co-immunoprecipitation showed that c-Jun was bound to nuclear ST2 under basal conditions; this complex was disrupted within 3 h of treatment, releasing c-Jun to activate IL-2 and miR-217 transcription before re-forming after 24 h. This transient release corresponds to the early induction of IL-2 and later reduction in KRAS levels.

Conclusions: Nerofe+ldDox reprograms the immune microenvironment of mtKRAS tumors by releasing c-Jun from inhibitory nuclear ST2, enabling expression of IL-2 and miR-217. This “nuclear immunomodulation” promotes immune cell infiltration and downregulates KRAS expression, highlighting Nerofe+ldDox as a promising therapeutic approach for mtKRAS-driven cancers.

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Keywords - cancer, mutant KRAS, Nerofe, ST2 Receptor, tumor immune microenvironment, nuclear immunomodulation

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