2. Academic Validation
  3. MAP4K4 regulates the immune landscape of pancreatic tumor microenvironment and provides an opportunity for immunotherapy

MAP4K4 regulates the immune landscape of pancreatic tumor microenvironment and provides an opportunity for immunotherapy

  • Cancer Lett. 2026 Apr 28:644:218336. doi: 10.1016/j.canlet.2026.218336.
Sunil Kumar Singh 1,  Sandeep Kumar 2,  Saket Jha 1,  Navin Viswakarma 1,  Harsh Vyas 1,  Piush Srivastava 1,  Rakesh Sathish Nair 1,  Sowdhamini Mahendiran 1,  Niraj Nag 1,  Periannan Sethupathi 1,  Basabi Rana 3,  Jose Trevino 4,  Ajay Rana 5
Affiliations

Affiliations

  • 1 Department of Surgery, College of Medicine, University of Illinois Chicago, 840 S. Wood Street, Chicago, IL, 60612, USA.
  • 2 Department of Surgery, College of Medicine, University of Illinois Chicago, 840 S. Wood Street, Chicago, IL, 60612, USA; University of Illinois Hospital and Health Sciences System Cancer Center, University of Illinois Chicago, Chicago, IL, 60612, USA.
  • 3 Department of Surgery, College of Medicine, University of Illinois Chicago, 840 S. Wood Street, Chicago, IL, 60612, USA; University of Illinois Hospital and Health Sciences System Cancer Center, University of Illinois Chicago, Chicago, IL, 60612, USA; Research Unit, Jesse Brown VA Medical Center, Chicago, IL, 60612, USA.
  • 4 Division of Surgical Oncology, Department of Surgery, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
  • 5 Department of Surgery, College of Medicine, University of Illinois Chicago, 840 S. Wood Street, Chicago, IL, 60612, USA; University of Illinois Hospital and Health Sciences System Cancer Center, University of Illinois Chicago, Chicago, IL, 60612, USA; Research Unit, Jesse Brown VA Medical Center, Chicago, IL, 60612, USA. Electronic address: [email protected].
PMID: 41707980 DOI: 10.1016/j.canlet.2026.218336
Abstract

Due to its widespread resistance to conventional therapy, Pancreatic Ductal Adenocarcinoma (PDAC) is expected to be the second most common cause of cancer-related death in the United States by 2030. One of the major impediments to therapeutic failure in PDAC is the presence of an immunosuppressive tumor microenvironment (TME). Here, we report the effect of MAP4K4 in regulating innate and adaptive immunity in PDAC-TME in KPC tumors. The IHC analyses revealed that the overexpression of MAP4K4 enhances tumor infiltration of macrophages and neutrophils, while decreasing the number of T cells in KPC PDAC tumors. Furthermore, treating KPC mice with the MAP4K4 pharmacological inhibitor GNE-495 decreased the number of tumor-infiltrating macrophages and neutrophils and increased T cell counts. The RT2 PCR array analysis revealed that treatment with GNE-495 decreased the expression of the co-stimulatory receptor 4-1BB gene in both peripheral and tumor-infiltrating T cells. The combined therapy of GNE-495 and a 4-1BB agonistic monoclonal antibody (mAb) demonstrated the presence of maximal cytotoxic T cells and tumor regression, associated with increased survival in KPC mice. Our study suggests that MAP4K4 regulates innate and adaptive immune cells in pancreatic TME, and pharmacological inhibition of MAP4K4 decreases tumor macrophage and neutrophil counts. Moreover, the rationalized approach of combining a MAP4K4 inhibitor and a 4-1BB agonist mAb induces a T cell-mediated antitumor response, and this combination could serve as a viable treatment for PDAC.

Keywords

CTLs; Immunotherapy; MAP4K4; PDAC; TME; Treg.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-100343
    99.49%, MAP4K4 Inhibitor