Combined siRNA Targeting IκBα and Stat6 Promotes Macrophage Reprogramming toward Cancer Immunotherapy

Abstract

Tumor-associated macrophages (TAMs) are central regulators of the tumor microenvironment (TME). Their polarization state can critically influence tumor development and treatment resistance. In the TME, the pro-tumor M2-like phenotype is the most prevalent among TAMs and contributes to tumor progression by promoting immunosuppression, angiogenesis, and metastasis. Thus, reprogramming TAMs from an M2 to an antitumor M1-like phenotype is a promising strategy to enhance cancer immunotherapy by inhibiting these processes, stimulating inflammatory responses, and activating cytotoxic immune cells. In this study, an array of small interfering RNA (siRNA) targeting candidate genes to repolarize macrophages, i.e., the inhibitor of nuclear factor kappa B alpha (IκBα), the colony-stimulating factor 1 receptor (Csf-1r), and the signal transducer and activator of transcription 6 (Stat6), was delivered by lipid nanoparticles (LNPs). While knockdown of all targeted genes was successful, silencing IκBα or Stat6 altered M1/M2 marker expression toward an M1-like polarization. Furthermore, combining IκBα and Stat6 produced the most effective macrophage reprogramming, achieving simultaneous downregulation of M2 markers and upregulation of M1 markers. Our data demonstrates that this dual-targeting strategy strongly induced potent reprogramming of M2-polarized macrophages, establishing it as a superior immunotherapeutic framework.

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BibTeX RIS

BibTeX

@article{gul2026combined,
  title = {{Combined siRNA Targeting IκBα and Stat6 Promotes Macrophage Reprogramming toward Cancer Immunotherapy}},
  author = {Sezen Gul and Juliette Vergnaud and Qinglin Wang and Mélanie Hery and Florent Dumont and Pauline Tran and Séverine Domenichini and Claudine Deloménie and Mengyuan Cao and Jihana Achour and Jean-Luc Perfettini and François Fay and Elias Fattal},
  journal = {Molecular Pharmaceutics},
  year = {2026},
  month = sep,
  doi = {10.1021/acs.molpharmaceut.6c00510},
  url = {https://hal.science/hal-05775656v1},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - Combined siRNA Targeting IκBα and Stat6 Promotes Macrophage Reprogramming toward Cancer Immunotherapy
AU  - Sezen Gul
AU  - Juliette Vergnaud
AU  - Qinglin Wang
AU  - Mélanie Hery
AU  - Florent Dumont
AU  - Pauline Tran
AU  - Séverine Domenichini
AU  - Claudine Deloménie
AU  - Mengyuan Cao
AU  - Jihana Achour
AU  - Jean-Luc Perfettini
AU  - François Fay
AU  - Elias Fattal
PY  - 2026
DA  - 2026/09/27
JO  - Molecular Pharmaceutics
DO  - 10.1021/acs.molpharmaceut.6c00510
UR  - https://hal.science/hal-05775656v1
AB  - Tumor-associated macrophages (TAMs) are central regulators of the tumor microenvironment (TME). Their polarization state can critically influence tumor development and treatment resistance. In the TME, the pro-tumor M2-like phenotype is the most prevalent among TAMs and contributes to tumor progression by promoting immunosuppression, angiogenesis, and metastasis. Thus, reprogramming TAMs from an M2 to an antitumor M1-like phenotype is a promising strategy to enhance cancer immunotherapy by inhibiting these processes, stimulating inflammatory responses, and activating cytotoxic immune cells. In this study, an array of small interfering RNA (siRNA) targeting candidate genes to repolarize macrophages, i.e., the inhibitor of nuclear factor kappa B alpha (IκBα), the colony-stimulating factor 1 receptor (Csf-1r), and the signal transducer and activator of transcription 6 (Stat6), was delivered by lipid nanoparticles (LNPs). While knockdown of all targeted genes was successful, silencing IκBα or Stat6 altered M1/M2 marker expression toward an M1-like polarization. Furthermore, combining IκBα and Stat6 produced the most effective macrophage reprogramming, achieving simultaneous downregulation of M2 markers and upregulation of M1 markers. Our data demonstrates that this dual-targeting strategy strongly induced potent reprogramming of M2-polarized macrophages, establishing it as a superior immunotherapeutic framework.
SN  - 1543-8384
SN  - 1543-8392
ER  -

Abstract

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