Succinate preserves CD8 T cell fitness to augment antitumor immunity.

Succinate, a tricarboxylic acid cycle intermediate, accumulates in tumors with succinate dehydrogenase (SDH) mutations. Although succinate is recognized for modulating CD8 T cell cytotoxicity, its impact on T cell differentiation remains poorly understood. Here, we reveal that succinate accumulation in tumors lacking the SDH subunit B (SDHB) enhanced tumor-reactive CD8 T cell-mediated immune responses.

Glycogen shepherd guides the hidden trail of pentose phosphate pathway.

In a recent Molecular Cell study, Zhou et al. elucidated how glycogenolysis-derived glucose-1-phosphate mediates source-specific routing of glucose-6-phosphate into the pentose phosphate pathway through allosteric activation of glucose-6-phosphate dehydrogenase and liquid-liquid phase separation-mediated metabolic compartments. This compartmentalized distribution enables efficient reduced nicotinamide adenine dinucleotide phosphate (NADPH) generation from glycogenolytic flux, promoting Tm cell persistence by maintaining redox homeostasis.

Tumor-instructed glutamine synthesis in cancer-associated fibroblasts promotes pro-tumor macrophages.

In the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) play a crucial role in promoting tumor progression by creating an immunosuppressive environment through cytokine secretion and antigen presentation. While previous studies have demonstrated that CAFs exhibit distinct metabolic profiles compared with normal fibroblasts, it remains unclear how these metabolic programs influence the immune landscape within tumors and which factors drive metabolic reprogramming in CAFs. Here, we found that glutamine synthesis by CAFs promotes the polarization of pro-tumorigenic tumor-associated macrophages (TAMs) and supports tumor growth by altering TAM composition, highlighting the pivotal role of CAFs in shaping the immunosuppressive TME.

Single-cell signaling network profiling during redox stress reveals dynamic redox regulation in immune cells.

In eukaryotic cells, reactive oxygen species (ROS) serve as crucial signaling components. ROS are potentially toxic, so constant adjustments are needed to maintain cellular health. Here we describe a single-cell, mass cytometry-based method that we call signaling network under redox stress profiling (SN-ROP) to monitor dynamic changes in redox-related pathways during redox stress.

Circadian metabolism in myeloid cells.

Circadian rhythms are fundamental regulators of physiological processes, including immune function. Recent insights uncover that not only lymphocytes but also myeloid cells possess intrinsic circadian clocks that govern their behavior and function. Emerging evidence highlights how circadian regulation of metabolism critically shapes the inflammatory and tissue-repair functions of myeloid subsets.

Meta-epigenetic shifts in T cell aging and aging-related dysfunction.

Epigenetic regulation, including DNA methylation and histone modifications, play a pivotal role in shaping T cell functionality throughout life. With aging, these epigenetic changes profoundly affect gene expression, altering T cell plasticity, activation, and differentiation. These modifications contribute significantly to immunosenescence, increasing susceptibility to infections, cancer, and autoimmune diseases.

Age-associated nicotinamide adenine dinucleotide decline drives CAR-T cell failure.

Chimeric antigen receptor (CAR) T cell therapy is one of the most promising cancer treatments. However, different hurdles are limiting its application and efficacy. In this context, how aging influences CAR-T cell outcomes is largely unknown.

Tumor-draining lymph nodes - friend or foe during immune checkpoint therapy?

The pivotal role of tumor-draining lymph nodes (TDLNs) in supporting antitumor immunity and serving as sites for cancer metastasis presents a clinical challenge: eliminate tumors while preserving antitumor immune responses. In this article, we explore the initiation of tumor-specific immune responses within lymph nodes (LNs), the immunocompromised microenvironment induced by tumors within LNs, and the crucial involvement of TDLNs in immunotherapy. Additionally, we examine the clinical prospects of modifying surgical procedures or therapy sequences to enhance the efficacy of cancer treatment.

Chimeric autoantibody receptor T cells clonally eliminate B cells producing autoantibodies against IFN-γ.

Neutralizing anti-interferon-γ (IFN-γ) autoantibodies (nAIGAs) impair IFN-γ-mediated immunity, predisposing patients with nAIGAs to infection by nontuberculous mycobacteria, , and other intracellular pathogens. Current clinical management relies on continuous antimicrobial therapy, with no treatment offering sustained benefits. Here, we developed human chimeric autoantibody receptor (CAAR) T cells targeting autoreactive B cells expressing nAIGA B cell receptors (BCRs) using an IFN-γ receptor-irresponsive IFN-γ variant as bait.

PLT012, a Humanized CD36-Blocking Antibody, Is Effective for Unleashing Antitumor Immunity Against Liver Cancer and Liver Metastasis.

Unlabelled: Tumor cells develop various strategies to evade immune surveillance, one of which involves altering the metabolic state of the tumor microenvironment. In response to metabolic stress in the tumor microenvironment, several tumor-infiltrating immune subsets upregulate CD36 to take up lipids. This leads to impaired antitumor immunity, as intratumoral regulatory T cells exhibit increased survival and suppressive activity, whereas CD8+ T cells become more susceptible to ferroptosis and exhaustion.

Age- and diet-instructed metabolic rewiring of the tumor-immune microenvironment.

The tumor-immune microenvironment (TIME) plays a critical role in tumor development and metastasis, as it influences the evolution of tumor cells and fosters an immunosuppressive state by intervening the metabolic reprogramming of infiltrating immune cells. Aging and diet significantly impact the metabolic reprogramming of the TIME, contributing to cancer progression and immune evasion. With aging, immune cell function declines, leading to a proinflammatory state and metabolic alterations such as increased oxidative stress and mitochondrial dysfunction, which compromise antitumor immunity.

Interferon-driven Metabolic Reprogramming and Tumor Microenvironment Remodeling.

IFNs play a critical role in cancer biology, including impacting tumor cell behavior and instructing the tumor microenvironment (TME). IFNs recently have been shown to reprogram tumor metabolism through distinct mechanisms. Furthermore, IFNs shape the TME by modulating immune cell infiltration and function, contributing to the intricate interaction between the tumor and stromal cells.

iMetAct: An integrated systematic inference of metabolic activity for dissecting tumor metabolic preference and tumor-immune microenvironment.

Metabolic enzymes play a central role in cancer metabolic reprogramming, and their dysregulation creates vulnerabilities that can be exploited for therapy. However, accurately measuring metabolic enzyme activity in a high-throughput manner remains challenging due to the complex, multi-layered regulatory mechanisms involved. Here, we present iMetAct, a framework that integrates metabolic-transcription networks with an information propagation strategy to infer enzyme activity from gene expression data.

Asparagine deprivation enhances T cell antitumour response in patients via ROS-mediated metabolic and signal adaptations.

Preclinical studies have shown that asparagine deprivation enhances T cell antitumour responses. Here we apply compassionate use of L-asparaginase, usually employed to treat blood malignancies, on patients with recurrent metastatic nasopharyngeal carcinoma. The use of L-asparaginase notably enhances immune-checkpoint blockade therapy in patients by strengthening CD8T cell fitness.

PPARβ/δ-orchestrated metabolic reprogramming supports the formation and maintenance of memory CD8 T cells.

The formation of memory T cells is a fundamental feature of adaptative immunity, allowing the establishment of long-term protection against pathogens. Although emerging evidence suggests that metabolic reprogramming is crucial for memory T cell differentiation and survival, the underlying mechanisms that drive metabolic rewiring in memory T cells remain unclear. Here, we found that up-regulation of the nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) instructs the metabolic reprogramming that occurs during the establishment of central memory CD8 T cells.

Circadian tumor infiltration and function of CD8 T cells dictate immunotherapy efficacy.

The quality and quantity of tumor-infiltrating lymphocytes, particularly CD8 T cells, are important parameters for the control of tumor growth and response to immunotherapy. Here, we show in murine and human cancers that these parameters exhibit circadian oscillations, driven by both the endogenous circadian clock of leukocytes and rhythmic leukocyte infiltration, which depends on the circadian clock of endothelial cells in the tumor microenvironment. To harness these rhythms therapeutically, we demonstrate that efficacy of chimeric antigen receptor T cell therapy and immune checkpoint blockade can be improved by adjusting the time of treatment during the day.

PGE inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function.

Expansion of antigen-experienced CD8 T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer. Interleukin-2 (IL-2) acts as a key regulator of CD8 cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability. Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses.

Immunosurveillance encounters cancer metabolism.

Tumor cells reprogram nutrient acquisition and metabolic pathways to meet their energetic, biosynthetic, and redox demands. Similarly, metabolic processes in immune cells support host immunity against cancer and determine differentiation and fate of leukocytes. Thus, metabolic deregulation and imbalance in immune cells within the tumor microenvironment have been reported to drive immune evasion and to compromise therapeutic outcomes.

Metabolic interplay: tumor macrophages and regulatory T cells.

The tumor microenvironment (TME) contains a complex cellular ecosystem where cancer, stromal, vascular, and immune cells interact. Macrophages and regulatory T cells (Tregs) are critical not only for maintaining immunological homeostasis and tumor growth but also for monitoring the functional states of other immune cells. Emerging evidence reveals that metabolic changes in macrophages and Tregs significantly influence their pro-/antitumor functions through the regulation of signaling cascades and epigenetic reprogramming.

Re-"Formate" T-cell Antitumor Responses.

Rowe and colleagues discover that one-carbon (1C) metabolism rewiring occurs upon T-cell activation to support proliferation and cytolytic activity in CD8+ T cells and that supplementation of 1C donor formate rescues the dysfunctional T cells and their responsiveness to anti-PD-1 in selective tumor-infiltrated T-cell subsets. This finding represents an attractive strategy to overcome a metabolic vulnerability in the tumor microenvironment and improve the efficacy of immune checkpoint blockade. See related article by Rowe et al.

Mitochondria Dictate Function and Fate of HSCs and T Cells.

Hematopoietic stem cells (HSC) and T cells are intimately related, lineage-dependent cell populations that are extensively used as therapeutic products for the treatment of hematologic malignancies and certain types of solid tumors. These cellular therapies can be life-saving treatments; however, their efficacies are often limited by factors influencing their activity and cellular properties. Among these factors is mitochondrial metabolism, which influences the function and fate commitment of both HSCs and T cells.

Functional polarization of tumor-associated macrophages dictated by metabolic reprogramming.

Macrophages are highly plastic in different tissues and can differentiate into functional subpopulations under different stimuli. Tumor-associated macrophages (TAMs) are one of the most important innate immune cells implicated in the establishment of an immunosuppressive tumor microenvironment (TME). Recent evidence pinpoints the critical role of metabolic reprogramming in dictating pro-tumorigenic functions of TAMs.

Regulatory circuits of mitophagy restrict distinct modes of cell death during memory CD8 T cell formation.

Mitophagy, a central process guarding mitochondrial quality, is commonly impaired in human diseases such as Parkinson's disease, but its impact in adaptive immunity remains unclear. The differentiation and survival of memory CD8 T cells rely on oxidative metabolism, a process that requires robust mitochondrial quality control. Here, we found that Parkinson's disease patients have a reduced frequency of CD8 memory T cells compared with healthy donors and failed to form memory T cells upon vaccination against COVID-19, highlighting the importance of mitochondrial quality control for memory CD8 T cell formation.