One-carbon metabolism shapes T cell immunity in cancer.

One-carbon metabolism (1CM), comprising folate metabolism and methionine metabolism, serves as an important mechanism for cellular energy provision and the production of vital signaling molecules, including single-carbon moieties. Its regulation is instrumental in sustaining the proliferation of cancer cells and facilitating metastasis; in addition, recent research has shed light on its impact on the efficacy of T cell-mediated immunotherapy. In this review, we consolidate current insights into how 1CM affects T cell activation, differentiation, and functionality. Furthermore, we delve into the strategies for modulating 1CM in both T cells and tumor cells to enhance the efficacy of adoptively transferred T cells, overcome metabolic challenges in the tumor microenvironment (TME), and maximize the benefits of T cell-mediated immunotherapy.

Suppression of the METTL3-m6A-integrin ß1 axis by extracellular acidification impairs T cell infiltration and antitumor activity.

The acidic metabolic byproducts within the tumor microenvironment (TME) hinder T cell effector functions. However, their effects on T cell infiltration remain largely unexplored. Leveraging the comprehensive The Cancer Genome Atlas dataset, we pinpoint 16 genes that correlate with extracellular acidification and establish a metric known as the "tumor acidity (TuAci) score" for individual patients. We consistently observe a negative association between the TuAci score and T lymphocyte score (T score) across various human cancer types. Mechanistically, extracellular acidification significantly impedes T cell motility by suppressing podosome formation. This phenomenon can be attributed to the reduced expression of methyltransferase-like 3 (METTL3) and the modification of RNA N6-methyladenosine (m6A), resulting in a subsequent decrease in the expression of integrin ß1 (ITGB1). Importantly, enforced ITGB1 expression leads to enhanced T cell infiltration and improved antitumor activity. Our study suggests that modulating METTL3 activity or boosting ITGB1 expression could augment T cell infiltration within the acidic TME, thereby improving the efficacy of cell therapy.

Unplanned reoperation after pulmonary surgery: Rate, risk factors and early outcomes at a single center.

Background: Unplanned reoperation is a potential risk factor for worse prognoses and reflects the quality of surgical treatment. This study compared the short-term outcomes between patients with and without reoperation and identified clinical factors predicting reoperation within 90 days following pulmonary surgery. Methods: Consecutive patients undergoing pulmonary resection from January 2012 to August 2021 at our institution were retrospectively reviewed. Clinical and operation-related data were collected and analyzed. Kaplan‒Meier, Cox hazard proportional regression, and propensity score matching were adopted for prognostic evaluation. Results: A total of 90263 patients were included: 247 (0.27%) patients required reoperation within 90 days. Patients undergoing unplanned reoperation had higher mortality and more postoperative complications than the nonreoperation group. Reoperation within 24 h was associated with reduced odds of mortality relative to reoperation beyond 24 h. Independent risk factors for unplanned reoperation were male sex, benign lung disease, specific surgical locations, lobectomy, and pneumonectomy. A history of smoking, pulmonary tuberculosis, intraoperative pleural adhesion, and postoperative complications were also identified as predisposing factors. The most common complication was hemorrhage in 75.7% (187 of 247). Conclusion: Our study found that unplanned reoperation was a rare but serious event that increased the risk of postoperative complications and mortality. We identified several risk factors that could be used to stratify patients according to their reoperation risk and suggest that high-risk patients should receive more intensive monitoring and preventive measures. Moreover, our study indicated that reoperating within 24 h could improve the outcomes for patients who needed reoperation.

Extracellular acidosis restricts one-carbon metabolism and preserves T cell stemness.

The accumulation of acidic metabolic waste products within the tumor microenvironment inhibits effector functions of tumor-infiltrating lymphocytes (TILs). However, it remains unclear how an acidic environment affects T cell metabolism and differentiation. Here we show that prolonged exposure to acid reprograms T cell intracellular metabolism and mitochondrial fitness and preserves T cell stemness. Mechanistically, elevated extracellular acidosis impairs methionine uptake and metabolism via downregulation of SLC7A5, therefore altering H3K27me3 deposition at the promoters of key T cell stemness genes. These changes promote the maintenance of a 'stem-like memory' state and improve long-term in vivo persistence and anti-tumor efficacy in mice. Our findings not only reveal an unexpected capacity of extracellular acidosis to maintain the stem-like properties of T cells, but also advance our understanding of how methionine metabolism affects T cell stemness.