bims-spamet 2026-06-14 papers

Cell. 2026 Jun 11. pii: S0092-8674(26)00570-2. [Epub ahead of print]189(12): 3506-3508

Cysteine's metabolic fork: Sulfur partitioning shapes T cell function.

T cells live or die by their metabolism, yet one nutrient can serve very different ends. In this issue of Cell, Kelly et al. show that cysteine's sulfur is partitioned between glutathione and iron-sulfur cluster synthesis. This routing drives CD8+ T cell proliferation, effector function, and anti-tumor immunity.

DOI: https://doi.org/10.1016/j.cell.2026.05.011

Sci Adv. 2026 Jun 12. 12(24): eaee0517

Targeting TMED4 enhances CD8+ T cell function and CAR T cell efficacy in solid tumors through the IRE1α-autophagy axis.

Endoplasmic reticulum stress (ERS) and autophagy regulate tumor-infiltrating T cell function and exhaustion, but the underlying mechanisms remain unclear. Here, we identified the ERS-related transmembrane protein TMED4 (transmembrane emp24 domain-containing 4) as a critical regulator of CD8+ T cell antitumor immunity. Tmed4 deletion in T cells enhanced antitumor responses by promoting CD8+ T proliferation, infiltration, and killing capacity, while reducing terminal exhaustion. Mechanistically, Tmed4 deficiency hyperactivated the inositol-requiring enzyme 1α (IRE1α)-X-box binding protein 1 (XBP1) axis and induced autophagy flux in an IRE1α-dependent manner. Genetic deletion of Ern1 (IRE1α) or Becn1 (Beclin1) impaired the antitumor effects of Tmed4 deficiency, underscoring the role of ERS and autophagy in CD8+ T cell function. Moreover, Tmed4-deficient chimeric antigen receptor T cells (CAR T cells) displayed improved antitumor immunity. Pharmacological inhibition of Tmed4 using antisense oligonucleotide also enhanced CD8+ T cell-mediated tumor control. In summary, our study reveals that TMED4 governs CD8+ T cell effector function and limits terminal exhaustion through IRE1α-driven autophagy, establishing TMED4 as a promising immunotherapeutic target for improving CAR T cell efficacy.

DOI: https://doi.org/10.1126/sciadv.aee0517

NPJ Syst Biol Appl. 2026 Jun 11. pii: 84. [Epub ahead of print]12(1):

Longitudinal spatial neutrophil profiling during ACT in murine melanoma reveals distinct lymph node infiltration patterns.

Gemma van der Voort, Maike Effern, Michelle C R Yong, Lukas Kiwitz, Roberta Turiello, Sonia Leonardelli, Susanna Ng, Dillon Corvino, Tobias Bald, Nicole Glodde, Kevin Thurley, Jan Hasenauer, Michael Hölzel.

Reactive neutrophil infiltration can restrain CD8+ T cell expansion in lymph nodes during adoptive T cell therapy (ACT), yet its spatiotemporal regulation remains incompletely understood. Levaraging flow cytometry and multiplex immunofluorescence data, we performed a time-resolved quantitative assessment of immune cell dynamics in tumor-draining lymph node (tdLN) and non-tumor-draining lymph node (non-tdLN) in a melanoma mouse model receiving ACT. Transferred tumor-reactive CD8+ T cells accumulated and expanded early after treatment initiation, showing the highest frequency of a favorable central memory 13 CD8+ T cell phenotype in the tdLN. Enhancing innate immune signaling in melanomas increased neutrophil influx into lymph nodes, particularly the non-tdLN; however, within the tdLN, neutrophils were enriched in the T cell zone, which also contained the largest absolute reservoir of transferred CD8+ T cells. Together, these findings indicate that tdLN and non-tdLN differ in early neutrophil dynamics and compartmentalization during ACT, influenced by the strength of innate immune signaling in the tumor.

DOI: https://doi.org/10.1038/s41540-026-00765-5

Phytomedicine. 2026 Jun 05. pii: S0944-7113(26)00614-8. [Epub ahead of print]158 158382

Quercetin targets BCAT1 to potentiate CD8+ T cell immunity by rewiring branched-chain amino acid metabolism against colorectal cancer metastasis.

Chuyi Wang, Yunxing Xu, Pengcheng Ding, Yunhai Ding, Liangfeng Zheng, Tianyi Li, Shouliang Cheng, Chen Zhang, Feiyue Ji, Xiaojiang Liu, Kai Chen, Guiyuan Gu, Xiaomin Lu.

Colorectal cancer (CRC) metastasis is a major cause of cancer‑related death, highlighting the need for therapies that target immune‑metabolic pathways. Here, we show that quercetin inhibits CRC progression via dual actions: directly suppressing tumor cell growth and migration, while systemically reinvigorating CD8+ T cell mediated immunity. In vitro, quercetin potently inhibited CRC cell proliferation, migration, and survival. In an experimental lung metastasis mouse model, quercetin enhanced the effector function of CD8+ T cells, as evidenced by increased production of Granzyme B, Perforin, and IFN-γ in metastases, blood, and tumor-draining lymph nodes. Metabolomic profiling uncovered a pronounced remodeling of branched-chain amino acid (BCAA) metabolism following quercetin intervention. Screening via the HERB database identified BCAA transaminase 1 (BCAT1) as a candidate target, confirmed by molecular docking and surface plasmon resonance (SPR). Importantly, the combination of oral leucine and quercetin produced a synergistic effect, significantly boosting CD8+ T cell cytotoxicity and dramatically reducing the lung metastatic burden. Taken together, these data identify BCAT1 as a direct target of quercetin and elucidate a resultant immunometabolic circuit that bolsters CD8+ T cell function, providing a rationale for targeting this pathway in advanced CRC.

Keywords: BCAT1; Branched-chain amino acid; Colorectal cancer metastasis; Quercetin

DOI: https://doi.org/10.1016/j.phymed.2026.158382

STAR Protoc. 2026 Jun 10. pii: S2666-1667(26)00274-1. [Epub ahead of print]7(2): 104621

Protocol for co-culture of murine bone marrow-derived dendritic cells with OT-I mouse CD8+ T cells to evaluate immune activation efficacy.

Min Jiang, Dana Matzek, Anny Nguyen, Bastian Popper, Olivia M Merkel.

Preliminary evaluation of vaccine-induced immune activation can be performed with minimal animal use, in line with the principles of the 3Rs (replacement, reduction, and refinement) in animal experimentation. Here, we present a protocol to assess murine antigen-specific CD8+ T cell activation using a co-culture model of bone marrow-derived dendritic cells (BMDCs) and OT-I transgenic CD8+ T cells. We describe the steps for transfecting BMDCs with antigen-encoding mRNA formulations and assessing T cell responses after co-culture by intracellular cytokine staining and proliferation. For complete details on the use and execution of this protocol, please refer to Jiang et al.1.

Keywords: Cell-based Assays; Health Sciences; Immunology; Model Organisms

DOI: https://doi.org/10.1016/j.xpro.2026.104621

Front Immunol. 2026 ;17 1810096

Spatial organization of the tumor immune microenvironment in LAR+ triple-negative breast cancer.

Donatella Lucchetti, Alba Di Leone, Giulia Sabbatinelli, Federica Toma, Franco Antonio, Beatrice Cellini, Filomena Colella, Erica Pazzaglia, Chiara Parrillo, Luciano Giacó, Angela Santoro, Alessia Piermattei, Rita Colonna, Gianluca Franceschini, Alessandro Sgambato.

Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease lacking approved targeted therapies and standardized treatment regimens. Among its molecular subtypes, luminal androgen receptor-positive (LAR+) TNBC is characterized by reduced proliferative activity and a lower sensitivity to chemotherapy. The tumor immune microenvironment (TIME) plays a critical role in shaping treatment responses; however, its spatial organization and cellular composition in LAR+ TNBC remain poorly understood.
Methods: In this exploratory study, we performed multiplex immunofluorescence analysis to characterize 18 immune and tumor cell subtypes in paired pre- and post-neoadjuvant therapy (NAT) samples from small, exploratory cohort of patients with LAR+ TNBC, stratified by pathological complete response (pCR). We assessed immune cell composition, expression of exhaustion markers, and spatial relationships among cellular populations to explore TIME features associated with different pathological responses.
Results: Patients who achieved pCR displayed higher pre-treatment densities of specific immune subsets, including CD20+PD-1+, CD4+FOXP3+, and CD8+PD-1+TIM3+ cells, consistent with an immune-enriched microenvironment. Spatial analyses revealed distinct patterns between Responders (Resp) and Non-Responders (NoResp). In Resp, tumor cells (PANCK+) were initially located closer to PD-L1-expressing tumor cells (PANCK+PD-L1+), with this proximity decreasing after NAT. In contrast, in non-Resp, immunosuppressive tumor cells moved closer to tumor cells following treatment. Moreover, NAT in Resp was associated with a spatial repositioning of CD4+ and CD8+ T cells toward tumor cells. B cells and regulatory B cells (Bregs) also exhibited differential spatial dynamics between the two groups.
Conclusions: This exploratory analysis describes distinct immune compositions and spatial arrangements of the TIME in LAR+ TNBC. Our findings suggest that specific immune enrichments and spatial remodeling patterns may differ between patients with different pathological outcomes, whereas the persistence of immunosuppressive niches characterizes non-Resp. Given the small sample size and the inclusion of immune checkpoint inhibitors in a subset of patients, all of whom achieved pCR, these observations should be considered strictly hypothesis-generating. Larger and more homogeneous cohorts will be required to validate these findings and to determine their potential clinical relevance.

Keywords: Breast cancer; LAR; TNBC (triple negative breast cancer); spatial proteomics; tumor microenvironment

DOI: https://doi.org/10.3389/fimmu.2026.1810096

NPJ Syst Biol Appl. 2026 Jun 13.

Spatial analysis of malignant-immune cell interactions in the tumor microenvironment using topological data analysis.

Seol Ah Park, Davide Gurnari, Paweł Dłotko, Yongsoo Kim, Jooyoung Hahn.

The spatial interactions between malignant and immune cells in the tumor microenvironment are important for tumor immunobiology and patient outcomes. However, analytical tools that can extract rigorous yet interpretable spatial features and link them to patient outcomes remain limited. We propose a framework integrating TDA with statistical approaches to extract interpretable spatial features characterizing malignant-immune interactions. We introduce Topological Malignant Region (TopMR), which uses topological persistence to automatically define regions of malignant cells, providing an objective reference for spatial analysis even when tumor boundaries are ambiguous. Global-scale infiltration is quantified using signed distances from immune cells to the TopMR boundary and local-scale interactions are captured via malignant cell density around individual immune cells. These global and local features are integrated into a unified signed distance-density (sDD) space, enabling comprehensive characterization of spatial patterns. We apply this framework to high-resolution multiplex immunofluorescence images of diffuse large B-cell lymphoma, analyzing both malignant-enriched and tumor border regions. Two-stage hierarchical clustering stratifies patients based on spatial interaction patterns, revealing associations with survival outcomes. This framework provides an end-to-end pipeline from spatial feature extraction to clinical interpretation, suggesting how region-aware spatial analysis can capture biologically meaningful patterns linked to patient survival.

DOI: https://doi.org/10.1038/s41540-026-00763-7