Intersection of immune and oncometabolic pathways drives cancer hyperprogression during immunotherapy

Li, Gaopeng; Choi, Jae Eun; Kryczek, Ilona; Sun, Yilun; Liao, Peng; Li, Shasha; Wei, Shuang; Grove, Sara; Vatan, Linda; Nelson, Reagan; Schaefer, Grace; Allen, Steven G.; Sankar, K. Nathan; Fecher, Leslie A.; Mendiratta‐Lala, Mishal; Qin, Angel; Waninger, Jessica; Tezel, Alangoya; Alva, Ajjai; Ramnath, Nithya; Cieślik, Marcin; Harms, Paul W.; Green, Michael D.; Chinnaiyan, Arul M.; Zou, Weiping

doi:10.1016/j.ccell.2022.12.008

Cited by 60 publications

(49 citation statements)

References 89 publications

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“…Patients with FGF3, FGF4 and FGF19 amplification tumors were reportedly more prone to HPD after immunotherapy [ 189 ]. A recent study has elucidated the molecular basis of HPD in ICI patients and indicated the key role of FGF-2 [ 190 ]. It unexpectedly found that patients with complete response and HPD exhibited similar levels of IFN-γ and Interferon Regulatory Factor 1(IRF1), as well as similar T-cell infiltration during immunotherapy, suggesting that patients with HPD are not exclusively associated with immune exclusion [ 190 ].…”

Section: Combination Of Fgfr-tki and Immune Checkpoint Therapymentioning

confidence: 99%

“…A recent study has elucidated the molecular basis of HPD in ICI patients and indicated the key role of FGF-2 [ 190 ]. It unexpectedly found that patients with complete response and HPD exhibited similar levels of IFN-γ and Interferon Regulatory Factor 1(IRF1), as well as similar T-cell infiltration during immunotherapy, suggesting that patients with HPD are not exclusively associated with immune exclusion [ 190 ]. IFN-γ is known to play a dual role in antitumor immunity and immune escape [ 58 , 191 , 192 ].…”

Section: Combination Of Fgfr-tki and Immune Checkpoint Therapymentioning

confidence: 99%

“…IFN-γ is known to play a dual role in antitumor immunity and immune escape [ 58 , 191 , 192 ]. The data also indicate that ICI can promote tumor growth in a CD8 + T-cell-dependent manner [ 190 ]. Thus, ICI may contribute to HPD by activating oncogenic pathways through IFN-γ signaling from T-cells [ 190 ].…”

Section: Combination Of Fgfr-tki and Immune Checkpoint Therapymentioning

confidence: 99%

“…The data also indicate that ICI can promote tumor growth in a CD8 + T-cell-dependent manner [ 190 ]. Thus, ICI may contribute to HPD by activating oncogenic pathways through IFN-γ signaling from T-cells [ 190 ]. Further experiments indicated that IFN-γ activated β-catenin signaling in HPD tumor cells as a result of it reducing NAD + levels to enhance β-catenin acetylation [ 190 ].…”

Section: Combination Of Fgfr-tki and Immune Checkpoint Therapymentioning

confidence: 99%

“…Thus, ICI may contribute to HPD by activating oncogenic pathways through IFN-γ signaling from T-cells [ 190 ]. Further experiments indicated that IFN-γ activated β-catenin signaling in HPD tumor cells as a result of it reducing NAD + levels to enhance β-catenin acetylation [ 190 ]. Moreover, IFN-γ phosphorylates M2 pyruvate kinase(PKM2) to an inactive form [ 190 ].…”

Section: Combination Of Fgfr-tki and Immune Checkpoint Therapymentioning

confidence: 99%

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Unleashing the potential of combining FGFR inhibitor and immune checkpoint blockade for FGF/FGFR signaling in tumor microenvironment

Ruan

et al. 2023

Mol Cancer

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Background Fibroblast growth factors (FGFs) and their receptors (FGFRs) play a crucial role in cell fate and angiogenesis, with dysregulation of the signaling axis driving tumorigenesis. Therefore, many studies have targeted FGF/FGFR signaling for cancer therapy and several FGFR inhibitors have promising results in different tumors but treatment efficiency may still be improved. The clinical use of immune checkpoint blockade (ICB) has resulted in sustained remission for patients. Main Although there is limited data linking FGFR inhibitors and immunotherapy, preclinical research suggest that FGF/FGFR signaling is involved in regulating the tumor microenvironment (TME) including immune cells, vasculogenesis, and epithelial-mesenchymal transition (EMT). This raises the possibility that ICB in combination with FGFR-tyrosine kinase inhibitors (FGFR-TKIs) may be feasible for treatment option for patients with dysregulated FGF/FGFR signaling. Conclusion Here, we review the role of FGF/FGFR signaling in TME regulation and the potential mechanisms of FGFR-TKI in combination with ICB. In addition, we review clinical data surrounding ICB alone or in combination with FGFR-TKI for the treatment of FGFR-dysregulated tumors, highlighting that FGFR inhibitors may sensitize the response to ICB by impacting various stages of the “cancer-immune cycle”.

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Section: Combination Of Fgfr-tki and Immune Checkpoint Therapymentioning

confidence: 99%

Section: Combination Of Fgfr-tki and Immune Checkpoint Therapymentioning

confidence: 99%

Section: Combination Of Fgfr-tki and Immune Checkpoint Therapymentioning

confidence: 99%

Section: Combination Of Fgfr-tki and Immune Checkpoint Therapymentioning

confidence: 99%

Section: Combination Of Fgfr-tki and Immune Checkpoint Therapymentioning

confidence: 99%

See 3 more Smart Citations

Unleashing the potential of combining FGFR inhibitor and immune checkpoint blockade for FGF/FGFR signaling in tumor microenvironment

Ruan

et al. 2023

Mol Cancer

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Apoptosis‐Sensitizing Tumor Nanomedicine by Regulating Pyroptosis‐Associated Inflammatory Cell Death

Du,

Zhao,

Song

et al. 2024

Adv Funct Materials

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The vigorous development of cancer nanomedicine has revolutionized traditional oncology medicine, but it is also limited by the continuous mutation of cunning cancer cells, leading to apoptosis insensitivity and therapeutic disappointment. Inflammatory‐regulated cell death (RCD), especially pyroptosis‐related cell death, demonstrates huge potential for apoptosis sensitization due to its unique biochemical characteristics. The aim of this research is to present a thorough synopsis of the current knowledge on pyroptosis‐associated inflammatory cell death, including pyroptosis, cuproptosis, and PANoptosis, and the synergistic function in cancer nano therapy. Paradigm studies of pyroptosis‐related cell death‐mediated apoptosis‐sensitizing tumor nanotherapeutics are introduced in detail, and the coordination mechanisms based on nanomaterials are also discussed. In addition, multi‐angle analysis of the future prospects of pyroptosis‐sensitized tumor nanomedicine based on various nanomaterials is also emphasized to further expand the application scope of inflammatory RCD. It is believed that emerging auxiliary apoptosis‐sensitizing treatments based on inflammatory RCD will greatly promote the progress of cancer nanomedicine.

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Lactylated Apolipoprotein C‐II Induces Immunotherapy Resistance by Promoting Extracellular Lipolysis

Chen,

Zhao,

Wang

et al. 2024

Advanced Science

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Mortality rates due to lung cancer are high worldwide. Although PD‐1 and PD‐L1 immune checkpoint inhibitors boost the survival of patients with non‐small‐cell lung cancer (NSCLC), resistance often arises. The Warburg Effect, which causes lactate build‐up and potential lysine‐lactylation (Kla), links immune dysfunction to tumor metabolism. The role of non‐histone Kla in tumor immune microenvironment and immunotherapy remains to be clarified. Here, global lactylome profiling and metabolomic analyses of samples from patients with NSCLC is conducted. By combining multi‐omics analysis with in vitro and in vivo validation, that intracellular lactate promotes extracellular lipolysis through lactyl‐APOC2 is revealed. Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing it and resulting in FFA release, regulatory T cell accumulation, immunotherapy resistance, and metastasis. Moreover, the anti‐APOC2K70‐lac antibody that sensitized anti‐PD‐1 therapy in vivo is developed. This findings highlight the potential of anti lactyl‐APOC2‐K70 approach as a new combination therapy for sensitizing immunotherapeutic responses.

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Intersection of immune and oncometabolic pathways drives cancer hyperprogression during immunotherapy

Cited by 60 publications

References 89 publications

Unleashing the potential of combining FGFR inhibitor and immune checkpoint blockade for FGF/FGFR signaling in tumor microenvironment

Unleashing the potential of combining FGFR inhibitor and immune checkpoint blockade for FGF/FGFR signaling in tumor microenvironment

Apoptosis‐Sensitizing Tumor Nanomedicine by Regulating Pyroptosis‐Associated Inflammatory Cell Death

Lactylated Apolipoprotein C‐II Induces Immunotherapy Resistance by Promoting Extracellular Lipolysis

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