Available online 26 February 2026

Author links open overlay panelCandelaria Aguilar-García a b c, Alejandra Martínez-Pérez a b c, Rocío Granda-Díaz a, Segundo Gonzalez a b cShow moreAbstract

Interferon-gamma (IFN-γ) is a pivotal cytokine that coordinates the immune response to infections caused by viruses and intracellular pathogens. Knockout (KO) mice lacking IFN-γ exhibited a significant reduction in the capacity of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells to eliminate tumor cells, resulting in accelerated tumor growth and metastasis. These findings underscore the key role of IFN-γ in regulating the antitumor immune response. However, many advanced tumors exhibit dysregulated IFN-γ signaling, which exerts direct protumoral and immunosuppressive effects, thereby allowing cancer cells to evade immune surveillance and promoting cancer progression. This dual role of IFN-γ in regulating cancer immunity has limited its therapeutic use in cancer. Understanding the specific conditions under which IFN-γ has an antitumoral or a protumoral role is a challenge for optimizing its use in cancer therapy.

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Access through your organizationSection snippetsIFN-γ in cancer immunity: Friend or foe?

Interferons (IFNs) are a family of cytokines that play a crucial role in the immune response to viral infection, cancer, and autoimmune disease. They are classified into three major types: type I, type II, and type III, each with distinct functions and receptors. Type I interferons include IFN-α and IFN-β, which are produced early by nucleated cells upon viral infection and are involved primarily in coordinating the immune antiviral responses (Dalskov et al., 2023). Type III interferons,

IFN-γ production

IFN-γ is a pleiotropic type II cytokine consisting of a homodimer formed by the noncovalent interaction of two polypeptide subunits of 17 kDa. IFN-γ is produced mainly by NK cells in innate immunity and by CD4+ Th1 cells, CTLs, and γδ T cells in adaptive immunity (Okamura et al., 1995, Peng et al., 2024, Hayakawa et al., 2011, Sood et al., 2019). In addition, NKT cells, B cells, and antigen-presenting cells (APCs) contribute to its production at lower levels (Frucht et al., 2001,

IFN-γ signaling

The IFN-γ receptor (IFNγR) is a member of the class II cytokine receptor family and consists of two subunits: IFNγR1 (α subunit) and IFNγR2 (β subunit). IFNγR1 is constitutively expressed on all nucleated cells. IFNγR2 is expressed at low levels but is induced by the transcription factors Sp1, AP-2, and NF-κB, allowing IFN-γ-induced signaling (Fig. 1A). As a result, IFNγR2 expression is a limiting factor in IFN-γ responsiveness in various cell types (Bernabei et al., 2001, Girdlestone and Wing,

Biological functions of IFN-γ

The majority of IFN-γ biological responses are initiated by the activation of the canonical JAK/STAT pathway, which has emerged as a critical pathway coordinating the immune response against intracellular pathogens with pleiotropic roles in both innate and adaptive immunity. Its primary function is to activate macrophages to enhance their microbicidal activity, thereby improving their ability to clear infections (Schroder et al., 2004, Gattoni et al., 2006). IFN-γ also polarizes macrophages to

IFN-γ-induced immune cell activation and cytotoxicity

IFN-γ is a key cytokine that promotes anticancer immunity and plays a pivotal role in determining the efficacy of immunotherapy (Han et al., 2023, Castro et al., 2018, Schroder et al., 2004, Boehm et al., 1997) (Fig. 2A). IFN-γ coordinates the innate and adaptive antitumor immune response activating macrophages, DCs, T cells, and NK cells. Moreover, IFN-γ inhibits Tregs, as well as the differentiation and functions of Th2 and Th17 cells, thereby reducing immune suppression in the TME (

From antitumorigenic to protumorigenic roles of IFN-γ in cancer

Despite its critical role in antitumor immunity (Chen et al., 2023, Benci et al., 2016, Benci et al., 2019, Castro et al., 2018), IFN-γ signaling may be exploited by advanced tumors to mount immune resistance, tumor progression, and survival rather than increasing their antigenicity and susceptibility to death (Zaidi & Merlino, 2011) (Fig. 2B). Tumors may become resistant to the antitumorigenic effects of IFN-γ by losing or inactivating key components of the IFN-γ signaling pathway avoiding its

IFN-γ in cancer immunotherapy

IFN-γ was approved by the Food and Drug Administration in 1999 for the treatment of chronic granulomatous disease. Since IFN-γ has been extensively studied as an immunotherapeutic agent in cancer, with varying response rates in different cancer types; however, its efficacy has been limited, particularly in solid tumors, and it has not yet been approved for any solid tumor indication (Kobayashi and Urabe, 1988, Zaidi and Merlino, 2011, Green et al., 2016, Aulitzky et al., 1989, Kurzrock et al.,

Concluding remarks

This chapter has emphasized that IFN-γ plays a dual role in cancer, acting as a key coordinator of cancer immune surveillance and, paradoxically, in certain tumors, as a facilitator of tumor progression and immune suppression. The current view of the field emphasizes that IFN-γ action depends on the tumor context, dose, and interaction with the TME. The field is moving towards the development of personalized medicine that modulates IFN-γ according to the tumor context. Therapeutic strategies

Acknowledgments and declaration of interests

This work was supported by a Spanish grant from Instituto de Salud Carlos III (PI23/01576) cofunded by the European Union, Government of the Principality of Asturias through the Agency for Science, Business Competitiveness, and Innovation of the Principality of Asturias and co-financed by the European Union through the Grants for Research Groups of Organizations of the Principality of Asturias, under file number IDE/2024/00074, Fundación Xti Xtod@s, Fundación Alimerka and Fundación LAIR. C.A-G

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