Cytokines of the common γ-chain family (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21) are pivotal in regulating immune responses and hold significant promise for cancer immunotherapy. However, their clinical efficacy has been hindered by short serum half-life, pleiotropic off-target effects, and dose-limiting systemic toxicities such as cytokine release syndrome. This review provides a comprehensive overview of recent advancements designed to overcome these limitations. Molecular engineering strategies, including PEGylation, Fc-fusion, muteins, and next-generation approaches like pro-cytokines and split-cytokines, which aim to enhance stability and receptor specificity. To minimize systemic toxicity and achieve high, tumor-localized cytokine concentrations, a variety of innovative delivery systems have been developed, ranging from polymer- and lipid-based nanoparticles to biological vehicles such as oncolytic viruses and cell-based therapies. Furthermore, these delivery systems are designed to respond to both intrinsic and extrinsic stimuli, enabling spatial and temporal control over cytokine activity. By synthesizing current progress and remaining challenges, this review outlines the future trajectory of cytokine-based therapeutics in achieving precise and safe anti-tumor immunity.

Regulatory T (Treg) cells are essential for maintaining immune homeostasis by suppressing excessive immune responses. In the context of cancer, however, Tregs promote immune evasion and tumor progression, particularly through their unique adaptations within the tumor microenvironment (TME). Recent research has emphasized how metabolic characteristics shape Treg activation, migration, and immunosuppressive function, revealing the impact of metabolic pathways on Treg fitness in homeostasis and within the TME. In this review, we first provide an overview of Tregs in cancer immunology, discussing their immunosuppressive roles and properties specific to the TME. We then examine the metabolic requirements for Treg activation and migration under normal conditions, followed by a discussion of how hypoxia, lactate accumulation, nutrient limitation, oxidative stress, and other TME-specific factors alter Treg metabolism and contribute to cancer immune evasion. Finally, we explore therapeutic strategies that target Treg metabolism within the TME, including pharmacological modulation of specific metabolic pathways to diminish Treg-mediated immunosuppression. Thus, we could suggest future directions and clinical implications for Treg-targeted metabolic modulation as a complementary approach in cancer treatment, setting the stage for novel strategies in immunotherapy.

The burgeoning field of immunometabolism highlights the interdependence between metabolic programs and efficacious immune responses. The current understanding that cellular metabolic remodeling is necessary for a competent adaptive immune response, along with acutely sensitive methodologies such as high-performance liquid chromatography/mass spectrometry and advanced proteomics, have ushered in a renaissance of lipid- and metabolic-based scientific inquiries. One facet of recent interest examines how lipids function as post-translational modifications (PTMs) and their resulting effects on adaptive immune responses. The goal of this review is to establish a fundamental understanding of these protein modifications and highlight recent findings that underscore the importance of continued investigation into lipids as PTMs.

Cigarette smoke extract (CSE)-treated mouse airway epithelial cells (MAECs)-derived exosomes accelerate the progression of chronic obstructive pulmonary disease (COPD) by upregulating triggering receptor expressed on myeloid cells 1 (TREM-1); however, the specific mechanism remains unclear. We aimed to explore the potential mechanisms of CSE-treated MAECs-derived exosomes on M1 macrophage polarization and pyroptosis in COPD. In vitro, exosomes were extracted from CSE-treated MAECs, followed by co-culture with macrophages. In vivo, mice exposed to cigarette smoke (CS) to induce COPD, followed by injection or/and intranasal instillation with oe-TREM-1 lentivirus. Lung function and pathological changes were evaluated. CD68+ cell number and the levels of iNOS, TNF-α, IL-1β (M1 macrophage marker), and pyroptosis-related proteins (NOD-like receptor family pyrin domain containing 3, apoptosis-associated speck-like protein containing a caspase-1 recruitment domain, caspase-1, cleaved-caspase-1, gasdermin D [GSDMD], and GSDMD-N) were examined. The expression of maternally expressed gene 3 (MEG3), spleen focus forming virus proviral integration oncogene (SPI1), methyltransferase 3 (METTL3), and TREM-1 was detected and the binding relationships among them were verified. MEG3 increased N6-methyladenosine methylation of TREM-1 by recruiting SPI1 to activate METTL3. Overexpression of TREM-1 or METTL3 negated the alleviative effects of MEG3 inhibition on M1 polarization and pyroptosis. In mice exposed to CS, EXO-CSE further aggravated lung injury, M1 polarization, and pyroptosis, which were reversed by MEG3 inhibition. TREM-1 overexpression negated the palliative effects of MEG3 inhibition on COPD mouse lung injury. Collectively, CSE-treated MAECs-derived exosomal long non-coding RNA MEG3 may expedite M1 macrophage polarization and pyroptosis in COPD via the SPI1/METTL3/TREM-1 axis.

In this review, we will explore the intricate roles of cytokines and vascular endothelial growth factors in autoimmune diseases (ADs), with a particular focus on rheumatoid arthritis (RA) and multiple sclerosis (MS). AD is characterized by self-destructive immune responses due to auto-reactive T lymphocytes and Abs. Among various types of ADs, RA and MS possess inflammation as a central role but in different sites of the patients. Other common aspects among these two ADs are their chronicity and relapsing-remitting symptoms requiring continuous management. First factor inducing these ADs are cytokines, such as IL-6, TNF-α, and IL-17, which play significant roles in the pathogenesis by contributing to inflammation, immune cell activation, and tissue damage. Secondly, vascular endothelial growth factors, including VEGF and angiopoietins, are crucial in promoting angiogenesis and inflammation in these two ADs. Finally, placental growth factor (PlGF), an emerging factor with bi-directional roles in angiogenesis and T cell differentiation, as we introduce as an "angio-lymphokine" is another key factor in ADs. Thus, while angiogenesis recruits more inflammatory cells into the peripheral sites, cytokines secreted by effector cells play critical roles in the pathogenesis of ADs. Various therapeutic interventions targeting these soluble molecules have shown promise in managing autoimmune pathogenic conditions. However, delicate interplay between cytokines, angiogenic factors, and PlGF has more to be studied when considering their complementary role in actual pathogenic conditions. Understanding the complex interactions among these factors provides valuable insights for the development of innovative therapies for RA and MS, offering hope for improved patient outcomes.

IL-15 belongs to the common gamma chain cytokine family and has pleiotropic immunological functions. IL-15 is a homeostatic cytokine essential for the development and maintenance of NK cells and memory CD8+ T cells. In addition, IL-15 plays a critical role in the activation, effector functions, tissue residency, and senescence of CD8+ T cells. IL-15 also activates virtual memory T cells, mucosal-associated invariant T cells and γδ T cells. Recently, IL-15 has been highlighted as a major trigger of TCR-independent activation of T cells. This mechanism is involved in T cell-mediated immunopathogenesis in diverse diseases, including viral infections and chronic inflammatory diseases. Deeper understanding of IL-15-mediated T-cell responses and their underlying mechanisms could optimize therapeutic strategies to ameliorate host injury by T cell-mediated immunopathogenesis. This review highlights recent advancements in comprehending the role of IL-15 in relation to T cell responses and immunopathogenesis under various host conditions.

Tregs play a central role in maintaining immune tolerance. Recent progress in the clinical application of Tregs underscores their potential for cell therapy. Nevertheless, a notable hurdle remains in producing functional Tregs in vitro. There is also a lack of detailed studies evaluating the function of Tregs during their ex vivo expansion process. Our prior investigation showed that the ex vivo expansion with oligonucleotides produces FoxP3highHelioshigh subsets. To investigate how oligonucleotides in culture media influence on gene expression and epigenetic states at single cell resolution, we sorted Tregs from healthy individuals and profiled in vitro oligonucleotide-expanded and non-expanded Tregs. We discovered a subset of Tregs, specifically enriched in expanded Tregs (seTregs), through oligonucleotide-induced expansion. seTregs showed an enhancement in both stem-like characteristics and functional attributes. Through analysis of histone modification data and gene regulatory networks, we elucidated IKZF2 (Helios) as a pivotal transcription factor in generating these cell subsets. We believe these findings offer insights into evaluating functional regulation of in vitro expanded Tregs aimed at manufacturing Treg-based cell therapies.

Defining the molecular dynamics associated with T cell differentiation enhances our understanding of T cell biology and opens up new possibilities for clinical implications. In this study, we investigated the dynamics of CD5 expression in CD8+ T cell differentiation and explored its potential clinical uses. Using PBMCs from 29 healthy donors, we observed a stepwise decrease in CD5 expression as CD8+ T cells progressed through the differentiation stages. Interestingly, we found that CD5 expression was initially upregulated in response to T cell receptor stimulation, but diminished as the cells underwent proliferation, potentially explaining the differentiation-associated CD5 downregulation. Based on the proliferation-dependent downregulation of CD5, we hypothesized that relative CD5 expression could serve as a marker to distinguish the heterogeneous CD8+ T cell population based on their proliferation history. In support of this, we demonstrated that effector memory CD8+ T cells with higher CD5 expression exhibited phenotypic and functional characteristics resembling less differentiated cells compared to those with lower CD5 expression. Furthermore, in the retrospective analysis of PBMCs from 30 non-small cell lung cancer patients, we found that patients with higher CD5 expression in effector memory T cells displayed CD8+ T cells with a phenotype closer to the less differentiated cells, leading to favorable clinical outcomes in response to immune checkpoint inhibitor (ICI) therapy. These findings highlight the dynamics of CD5 expression as an indicator of CD8+ T cell differentiation status, and have implications for the development of predictive biomarker for ICI therapy.

Immune diversification helps protect the host against a myriad of pathogens. CD8+ T cells are essential adaptive immune cells that inhibit the spread of pathogens by inducing apoptosis in infected host cells, ultimately ensuring complete elimination of infectious pathogens and suppressing disease development. Accordingly, numerous studies have been conducted to elucidate the mechanisms underlying CD8+ T cell activation, proliferation, and differentiation into effector and memory cells, and to identify various intrinsic and extrinsic factors regulating these processes. The current knowledge accumulated through these studies has led to a huge breakthrough in understanding the existence of heterogeneity in CD8+ T cell populations during immune response and the principles underlying this heterogeneity. As the heterogeneity in effector/memory phases has been extensively reviewed elsewhere, in the current review, we focus on CD8+ T cells in a “naïve” state, introducing recent studies dealing with the heterogeneity of naive CD8+ T cells and discussing the factors that contribute to such heterogeneity. We also discuss how this heterogeneity contributes to establishing the immense complexity of antigen-specific CD8+ T cell response.

Bacillus Calmette-Guerin (BCG) vaccine is the only licensed vaccine for tuberculosis (TB) prevention. Previously, our group demonstrated the vaccine potential of Rv0351 and Rv3628 against Mycobacterium tuberculosis (Mtb) infection by directing Th1-biased CD4+ T cells co-expressing IFN-γ, TNF-α, and IL-2 in the lungs. Here, we assessed immunogenicity and vaccine potential of the combined Ags (Rv0351/Rv3628) formulated in different adjuvants as subunit booster in BCG-primed mice against hypervirulent clinical Mtb strain K (Mtb K). Compared to BCG-only or subunit-only vaccine, BCG prime and subunit boost regimen exhibited significantly enhanced Th1 response. Next, we evaluated the immunogenicity to the combined Ags when formulated with four different types of monophosphoryl lipid A (MPL)-based adjuvants: 1) dimethyldioctadecylammonium bromide (DDA), MPL, and trehalose dicorynomycolate (TDM) in liposome form (DMT), 2) MPL and Poly I:C in liposome form (MP), 3) MPL, Poly I:C, and QS21 in liposome form (MPQ), and 4) MPL and Poly I:C in squalene emulsion form (MPS). MPQ and MPS displayed greater adjuvancity in Th1 induction than DMT or MP did. Especially, BCG prime and subunit-MPS boost regimen significantly reduced the bacterial loads and pulmonary inflammation against Mtb K infection when compared to BCG-only vaccine at a chronic stage of TB disease. Collectively, our findings highlighted the importance of adjuvant components and formulation to induce the enhanced protection with an optimal Th1 response.