Inhibiting KRAS with CD47 and immune checkpoint overcomes intrinsic resistance to combined KRAS and immune checkpoint inhibitor therapy
Although Kirsten rat sarcoma virus (KRAS) G12C inhibitors alter the treatment strategy for patients with KRAS G12C-mutant lung cancer, their efficacy remains insufficient to eliminate tumors. Here, we identify that inhibition of mutant KRAS promotes escape from macrophage phagocytosis by upregulating the expression of cluster of differentiation 47 (CD47) and CD24. These proteins are induced by the binding of FOXA1 to the super-enhancer of CD47 and grainyhead-like transcription factor 2 (GRHL2) to the promoter of CD24, respectively. Whereas the addition of an anti-CD47 antibody restores macrophage phagocytosis, phagocytic macrophages induce programmed death-ligand 1 (PD-L1) expression, resulting in the suppression of CD8 T cell activation. Combination of a KRAS inhibitor with anti-CD47 and anti-PD-L1 antibodies achieves long-term survival in an orthotopic murine model recalcitrant to KRAS inhibition with immune checkpoint therapy. These results suggest that targeting KRAS with an anti-CD47 antibody and immune checkpoint blockade is a promising strategy, especially in immune-cold lung tumors.
Authors
- Yuta Adachi (ORCID: https://orcid.org/0000-0003-1745-5039)
- Yuki Nishioka
- Shogo Yanase
- Kentaro Hirade (ORCID: https://orcid.org/0000-0003-3606-7250)
- Yoshihiko Sakata (ORCID: https://orcid.org/0000-0002-3300-9138)
- Ryo Kimura (ORCID: https://orcid.org/0000-0003-3220-991X)
- Taisuke Kajino (ORCID: https://orcid.org/0000-0002-4826-7690)
- Takahiko Sato (ORCID: https://orcid.org/0000-0003-3836-7978)
- Takaomi Sanda (ORCID: https://orcid.org/0000-0003-1621-4954)
- Masahiro Aoki (ORCID: https://orcid.org/0000-0003-4316-9490)
- Kageaki Watanabe (ORCID: https://orcid.org/0000-0002-8420-5606)
- Teruaki Fujishita (ORCID: https://orcid.org/0000-0002-4397-2438)
- Satoru Kisoda
- Daisuke Muraoka (ORCID: https://orcid.org/0000-0003-0901-5850)
- Rui Yamaguchi (ORCID: https://orcid.org/0000-0003-1224-227X)
- Hirokazu Matsushita
- Tze King Tan (ORCID: https://orcid.org/0000-0003-1623-615X)
- K. Tsuchiya (ORCID: https://orcid.org/0000-0001-8540-6920)
- Yoko Kitaura
- Hiromichi Ebi (ORCID: https://orcid.org/0000-0003-3155-7576)
- Osamu Muto (ORCID: https://orcid.org/0000-0003-3831-7612)
- Takamasa Yamamoto
- S. Hayakawa
- Shinsuke Iida
- Natsumi Kasuga
- Noritaka Tanaka
- Hitomi Kasuya
Institutions
- Kanazawa University (JP)
- National University of Singapore (SG)
- Tokyo Metropolitan Komagome Hospital (JP)
- Nagoya City University (JP)
- Saiseikai Kumamoto Hospital (JP)
- National University Cancer Institute, Singapore (SG)
- Aichi Cancer Center (JP)
- Nagoya University (JP)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-08-29
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102317
- Citations
- 2
- Primary Topic
- Phagocytosis and Immune Regulation
- Type
- article
- Field-Weighted Citation Impact
- 1.59