Cancer cells adeptly manipulate their metabolic processes to evade immune detection, a phenomenon intensifying the complexity of cancer progression and therapy. This review delves into the critical role of cancer cell metabolism in the immune-editing landscape, highlighting how metabolic reprogramming facilitates tumor cells to thrive despite immune surveillance pressures. We explore the dynamic interactions within the tumor microenvironment (TME), where cancer cells not only accelerate their glucose and amino acid metabolism but also induce an immunosuppressive state that hampers effective immune response. Recent findings underscore the metabolic competition between tumor and immune cells, particularly focusing on how this interaction influences the efficacy of emerging immunotherapies. By integrating cutting-edge research on the metabolic pathways of cancer cells, such as the Warburg effect and glutamine addiction, we shed light on potential therapeutic targets. The review proposes that disrupting these metabolic pathways could enhance the response to immunotherapy, offering a dual-pronged strategy to combat tumor growth and immune evasion.

(1) Background: Although the important role of dietary energy intake in regulating both cancer progression and host immunity has been widely recognized, it remains unclear whether dietary calorie restriction (CR) has any impact on anti-tumor immune responses. (2) Methods: Using an immunogenic B16 melanoma cell expressing ovalbumin (B16-OVA), we examined the effect of the CR diet on B16-OVA tumor growth and host immune responses. To further test whether the CR diet affects the efficacy of cancer immunotherapy, we examined the effect of CR against anti-PD-1 monoclonal antibody (anti-PD-1 Ab) treatment. (3) Results: The CR diet significantly slowed down the tumor growth of B16-OVA without affecting both CD4⁺ and CD8⁺ T cell infiltration into the tumor. Although in vivo depletion of CD8⁺ T cells facilitated B16-OVA tumor growth in the control diet group, there was no significant change in the tumor growth in the CR diet group with or without CD8⁺ T cell-depletion. Anti-PD-1 Ab treatment lost its efficacy to suppress tumor growth along with the activation and metabolic shift of CD8⁺ T cells under CR condition. (4) Conclusions: Our present results suggest that a physical condition restricted in energy intake in cancer patients may impair CD8⁺ T cell immune surveillance and the efficacy of immunotherapy.

Among factors involved in cancer cells escaping from immune responses, an intrinsic defect in the IFNγ response is considered to be one of the major players allowing cancer cells to evade the host immunity. In this study, we investigated how tumor cells escape from the IFNγ-dependent immune response through the immunoediting process by analyzing originally established immune-escape variants of melanoma cells. We found that the immune-escape melanoma variants gained resistance to the IFNγ-induced oxidative stress response and identified glutathione-S-transferase-4 (GSTA4) as a critical molecule in this process. Furthermore, the immune escape melanoma variants acquired a greater metastatic ability by a GSTA4-dependent mechanism. Implications: Considering the importance of GSTA4 in controlling IFNγ responsiveness and the metastatic potential of other melanoma cells, our results highlight a novel mechanism whereby cancer cells escape from host immunity and gain metastatic ability by acquiring resistance to oxidative stress responses through the upregulation of GSTA4.

Cancer immunotherapy has demonstrated remarkable clinical success across diverse tumor types. Nevertheless, durable responses occur in only a subset of patients, and both primary and acquired resistance remain major challenges. Interferon-γ (IFN-γ), a key effector cytokine in anti-tumor immunity, is often neutralized by tumor cells through mechanisms that attenuate its activity. In this study, we examined the regulation of IFN-γ responsiveness in two human NSCLC cell lines, PC-9 and A549. PC-9 cells exhibited greater resistance to IFN-γ treatment compared with A549 cells. Transcriptomic analysis revealed that IFN-γ–resistant PC-9 cells were enriched in genes associated with the homologous recombination (HR) DNA repair pathway following exposure to IFN-γ. Given the critical role of the serine/threonine kinase ataxia telangiectasia mutated (ATM) in detecting DNA double-strand breaks and coordinating HR repair, we investigated whether ATM contributes to IFN-γ resistance by using the ATM inhibitor KU-55933. Inhibition of ATM restored IFN-γ sensitivity by inducing ferroptosis in NSCLCs. Mechanistically, the combination of IFN-γ treatment and ATM inhibition elicited a robust DNA damage response and disrupted glutathione metabolism, reducing the GSH/GSSG ratio and thereby promoting ferroptosis through increased susceptibility to oxidative stress. These findings highlight the pivotal role of DNA damage response pathways in mediating the anti-tumor effects of IFN-γ.

S1. Establishment of immune-escape variants of B16OVA cells S2. Immune-escape variants of B16OVA cells respond to IFN-gamma S3. Establishment of GSTA4 over-expressing B16OVA cells and GSTA4 knock-down IMM2 cells S4. Tumor-infiltrating T cell population in IMM2 shCTRL and IMM2 shGSTA4 tumors S5. Expression of GSTA4 in metastatic B16 melanoma variants

S1. Establishment of immune-escape variants of B16OVA cells S2. Immune-escape variants of B16OVA cells respond to IFN-gamma S3. Establishment of GSTA4 over-expressing B16OVA cells and GSTA4 knock-down IMM2 cells S4. Tumor-infiltrating T cell population in IMM2 shCTRL and IMM2 shGSTA4 tumors S5. Expression of GSTA4 in metastatic B16 melanoma variants