Cancer Res Treat.  2025 Jan;57(1):1-10. 10.4143/crt.2024.255.

Role of HIF-1α in the Responses of Tumors to Radiotherapy and Chemotherapy

• Song CW
• Kim H
• Kim MS
• Park HJ
• Paek SH
• Terezakis S
• Cho LC

• KMID: 2564575
• DOI: http://doi.org/10.4143/crt.2024.255

Abstract

Tumor microenvironment is intrinsically hypoxic with abundant hypoxia-inducible factors-1α (HIF-1α), a primary regulator of the cellular response to hypoxia and various stresses imposed on the tumor cells. HIF-1α increases radioresistance and chemoresistance by reducing DNA damage, increasing repair of DNA damage, enhancing glycolysis that increases antioxidant capacity of tumors cells, and promoting angiogenesis. In addition, HIF-1α markedly enhances drug efflux, leading to multidrug resistance. Radiotherapy and certain chemotherapy drugs evoke profound anti-tumor immunity by inducing immunologic cell death that release tumor-associated antigens together with numerous pro-immunological factors, leading to priming of cytotoxic CD8+ T cells and enhancing the cytotoxicity of macrophages and natural killer cells. Radiotherapy and chemotherapy of tumors significantly increase HIF-1α activity in tumor cells. Unfortunately, HIF-1α effectively promotes various immune suppressive pathways including secretion of immune suppressive cytokines, activation of myeloid-derived suppressor cells, activation of regulatory T cells, inhibition of T cells priming and activity, and upregulation of immune checkpoints. Consequently, the anti-tumor immunity elevated by radiotherapy and chemotherapy is counterbalanced or masked by the potent immune suppression promoted by HIF-1α. Effective inhibition of HIF-1α may significantly increase the efficacy of radiotherapy and chemotherapy by increasing radiosensitivity and chemosensitivity of tumor cells and also by upregulating anti-tumor immunity.

Keyword

HIF-1α; Immunologic cell death; Radiotherapy; Chemotherapy; Radiosensitivity; Chemosensitivity; Anti-tumor immunity; Immunosuppression

Figure

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  Fig. 1. Effects of hypoxia-inducible factors-1α on various molecular and physiological factors involved in radioresistance and chemoresistance.

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  Fig. 2. Radiotherapy and chemotherapy elevate anti-tumor immunity by inducing immunologic cell death (ICD), leading to release of tumor-associated antigens (TAA) together with damage-associated molecular patterns (DAMPs). DAMP subsequently activates dendric cells (DCs), which then engulf TAAs, migrate to nearby lymph nodes, and prime T cells specific for TAA. The activated cytotoxic T cells (CTLs) subsequently migrate to residual tumors or metastatic tumors, and kill the tumor cells. Intratumor microenvironment is intrinsically hypoxic, which is further increased by radiotherapy and chemotherapy. The hypoxic tumor microenvironment activates hypoxiainducible factors-1α (HIF-1α), which stimulate various immunosuppressive pathways. Consequently, the elevated anti-tumor immunity caused by radiotherapy or chemotherapy is counterbalanced or offset by the potent immune suppressive reactions mediated by HIF-1α. CRT, calreticulin; HMGB1, high mobility group box 1 protein; HSP, heat shock protein; IFN, interferon; IR, irradiation; MDSC, myeloid-derived suppressor cell; MHC1, major histocompatibility complex class 1; TAM, tumor-associated macrophage; TCR, receptors on naïve T cells.

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  Fig. 3. Effects of hypoxia-inducible factors-1α on the expression or function of various immunological factors. CTLA-4, cytotoxic T-lymphocyte-associated antigen-4; DC, dendric cell; FasL, Fas ligand; IFN, interferon; IL-10, interleukin 10; MDSC, myeloid-derived suppressor cell; NK, natural killer; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; SDF1, stromal cell-derived factor 1; TAM, tumor-associated macrophage; TGF-β, transforming growth factor β; Treg, regulatory T cell; VEGF, vascular endothelial growth factor.

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  Fig. 4. The interrelationship among radiotherapy, chemotherapy, anti-tumor immunity, and hypoxia-inducible factors-1α (HIF-1α). Radiotherapy enhances the effectiveness of many chemotherapy drugs, and many chemotherapy drugs enhance the effectiveness of radiotherapy. Radiotherapy, particularly high-dose hypo-fractionated radiotherapy, and chemotherapy evoke anti-tumor immunity via induction of immunologic cell death. However, radiotherapy and chemotherapy also upregulate HIF-1α, which promote various immune suppressive reactions in tumor microenvironment, counterbalancing or offsetting the anti-tumor immunity. HIF-1α also diminishes the effectiveness of radiotherapy and chemotherapy.

Reference

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