TAM-tastic: from resistance to resilience in cancer.

Overcoming resistance to immunotherapy in cancer is challenging due, in part, to tumor-associated macrophages (TAMs) co-expressing T cell immunoglobulin and mucin domain-containing 3 (TIM3) and V-domain immunoglobulin suppressor of T cell activation (VISTA) in tumor microenvironments (TME) with sparse T cell infiltration. In a recent article, Vanmeerbeek et al. found that blocking TIM3 or VISTA on IL-4-supported TAMs, in combination with paclitaxel (PTX), reprogrammed TAMs to attack cancer cells, highlighting a potential new therapeutic strategy.

Active nitrogen sites on nitrogen doped carbon for highly efficient associative ammonia decomposition.

Nitrogen doped carbon materials have been studied as catalyst support for ammonia decomposition. There are 4 different types of nitrogen environments (graphitic, pyrrolic, pyridinic and nitrogen oxide) on the amorphous support identified. In this paper, we report a 5%Ru on MgCO3 pre-treated nitrogen doped carbon catalyst with high content of edge nitrogen-containing sites which displays an ammonia conversion rate of over 90% at 500°C and WHSV = 30,000 mL gcat -1 h-1. It also gives an impressive hydrogen production rate of 31.3 mmol/(min gcat) with low apparent activation energy of 43 kJ mol-1. Fundamental studies indicate that the distinct average Ru-N4 coordination site on edge regions is responsible for such high catalytic activity. Ammonia is stepwise decomposed via a Ru-N(H)-N(H)-Ru intermediate. This associative mechanism circumvents the direct cleavage of energetic surface nitrogen from metal to form N2 hence lowering the activation barrier for the decomposition over this catalyst.

PPARß/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 ß/δ (PPARß/δ) instructs the metabolic reprogramming that occurs during the establishment of central memory CD8+ T cells. PPARß/δ-regulated changes included suppression of aerobic glycolysis and enhancement of oxidative metabolism and fatty acid oxidation. Mechanistically, exposure to interleukin-15 and expression of T cell factor 1 facilitated activation of the PPARß/δ pathway, counteracting apoptosis induced by antigen clearance and metabolic stress. Together, our findings indicate that PPARß/δ is a master metabolic regulator orchestrating a metabolic switch that may be favorable for T cell longevity.

Understanding the impact of tourist behavior change on travel agencies in developing countries: Strategies for enhancing the tourist experience.

The study investigates the impact of tourist behavior change on travel agencies in developing countries, with a focus on strategies for enhancing the tourist experience. The research aims to identify the main factors influencing tourist purchasing behavior and understand their relationship with the customer experience. Data were collected from 368 experienced tourists in Ho Chi Minh City and Hanoi, Vietnam, using a combination of convenience and random sampling. Partial Least Squares Structural Equation modeling (PLS-SEM) is employed to analyze the research model. The findings confirm that product quality, product price, brand image, and marketing strategy significantly influence tourist purchasing behavior. Importantly, the results highlight the indirect effect of these factors on purchasing behavior, mediated through customer experience. It suggests that enhancing the customer experience is a crucial aspect of influencing tourist purchasing decisions. Based on these findings, industry managers and travel agents in developing countries should prioritize enhancing customer experience and building a strong brand through personalized services, digital integration, and active social media engagement. Implementing dynamic pricing strategies and targeted marketing campaigns that address safety concerns and highlight local experiences are crucial for competitiveness and attracting travelers post-crisis. Future research should explore the long-term effects of these strategies on travel agency performance and adapt the model to specific regional contexts. By adopting these multifaceted approaches, travel agencies in developing countries can enhance their competitiveness and better navigate the changing tourist behavior in the post-crisis era.

Stabilization of Ni-containing Keggin-type polyoxometalates with variable oxidation states as novel catalysts for electrochemical water oxidation.

The development of new recyclable and inexpensive electrochemically active species for water oxidation catalysis is the most crucial step for future utilization of renewables. Particularly, transition metal complexes containing internal multiple, cooperative metal centers to couple with redox catalysts in the inorganic Keggin-type polyoxometalate (POM) framework at high potential or under extreme pH conditions would be promising candidates. However, most reported Ni-containing POMs have been highly unstable towards hydrolytic decomposition, which precludes them from application as water oxidation catalysts (WOCs). Here, we have prepared new tri-Ni-containing POMs with variable oxidation states by charge tailored synthetic strategies for the first time and developed them as recyclable POMs for water oxidation catalysts. In addition, by implanting corresponding POM anions into the positively charged MIL-101(Cr) metal-organic framework (MOF), the entrapped Ni2+/Ni3+ species can show complete recyclability for water oxidation catalysis without encountering uncontrolled hydrolysis of the POM framework. As a result, a low onset potential of approximately 1.46 V vs. NHE for water oxidation with stable WOC performance is recorded. Based on this study, rational design and stabilization of other POM-electrocatalysts containing different multiple transition metal centres could be made possible.

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. Furthermore, time-of-day-dependent T cell signatures in murine tumor models predict overall survival in patients with melanoma and correlate with response to anti-PD-1 therapy. Our data demonstrate the functional significance of circadian dynamics in the tumor microenvironment and suggest the importance of leveraging these features for improving future clinical trial design and patient care.

PGE2 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 cancer1. Interleukin-2 (IL-2) acts as a key regulator of CD8+ cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability2,3. 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. Here we report that prostaglandin E2 (PGE2), a known negative regulator of immune response in the tumour microenvironment4,5, is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8+ TILs via the PGE2 receptors EP2 and EP4. Mechanistically, PGE2 inhibits IL-2 sensing in TILs by downregulating the IL-2Rγc chain, resulting in defective assembly of IL-2Rß-IL2Rγc membrane dimers. This results in impaired IL-2-mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE2 signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE2 in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential.

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. Interestingly, emerging evidence indicates that anti-tumor immunity could modulate tumor heterogeneity, aggressiveness, and metabolic reprogramming, suggesting that immunosurveillance can instruct cancer progression in multiple dimensions. This review summarizes our current understanding of how metabolic crosstalk within tumors affects immunogenicity of tumor cells and promotes cancer progression. Furthermore, we explain how defects in the metabolic cascade can contribute to developing dysfunctional immune responses against cancers and discuss the contribution of immunosurveillance to these defects as a feedback mechanism. Finally, we highlight ongoing clinical trials and new therapeutic strategies targeting cellular metabolism in cancer.

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. Hence, they are increasingly recognized as therapeutic targets in cancer immunotherapy. Specific metabolites in the TME may also affect their pro-/antitumor functions by intervening with the metabolic machinery. We discuss how metabolites influence the immunosuppressive phenotypes of tumor-associated macrophages (TAMs) and Tregs. We then describe how TAMs and Tregs, independently or collaboratively, utilize metabolic mechanisms to suppress the activity of CD8+ T cells. Finally, we highlight promising metabolic interventions that can improve the outcome of current cancer therapies.