bims-spamet 2026-07-12 papers

Front Immunol. 2026 ;17 1862431

Tumor-driven stabilization of CD8+ T cell exhaustion and implications for cancer immunotherapy.

Romane Thouenon, Marco Ongaro, Grégory Verdeil.

CD8+ T cell exhaustion is a conserved differentiation program induced by persistent antigen stimulation and originally characterized in chronic infection. In cancer, this program is actively reinforced and stabilized by the tumor microenvironment. Here, we examine how tumors convert a physiological adaptation to chronic stimulation into a deeply entrenched dysfunctional state. Sustained TCR signaling initiates exhaustion through NFAT- and TOX-dependent transcriptional remodeling, but tumor-specific extrinsic pressures, including hypoxia, metabolic competition, ionic imbalance, mechanical stress, and heterogeneous antigen exposure, amplify and stabilize this program. These environmental cues converge on transcription factor networks such as IRF, BATF, NR4A, and NFAT5, which integrate chronic signaling with stress-adaptive responses and progressively restrict effector potential. Exhaustion in tumors becomes epigenetically imprinted. Exhaustion-specific enhancer landscapes persist despite PD-1 blockade, reflecting a lineage-like state enforced by chromatin remodeling factors such as TOX. Thus, checkpoint inhibition transiently restores function without fully reprogramming cellular identity. We propose that tumor-induced exhaustion arises from the layered convergence of chronic antigen signaling and microenvironmental reinforcement, culminating in chromatin fixation. Understanding this stabilization process reframes therapeutic strategies: effective cancer immunotherapy will likely require combinatorial approaches that target not only inhibitory receptors but also metabolic resilience, stress-sensing pathways, and epigenetic architecture. By dissecting how tumors convert adaptive restraint into durable dysfunction, new avenues may emerge to destabilize exhaustion and restore durable antitumor immunity.

Keywords: T cell exhaustion; cancer; immunotherapies; transcriptional imprinting; tumor microenvironment

DOI: https://doi.org/10.3389/fimmu.2026.1862431

Trends Immunol. 2026 Jul 08. pii: S1471-4906(26)00161-4. [Epub ahead of print]

Adenosine as a metabolic checkpoint in CD8+ T cell dysfunction.

Arden O Edgerton, Mauricio J Reginato, Michele A Kutzler, Eilas K Haddad.

CD8+ T cell dysfunction, characterized by impaired effector function, proliferative capacity, and sustained inhibitory receptor expression, limits immune control in both cancer and chronic viral infections. Despite arising from distinct disease processes, these conditions induce a shared state of CD8+ T cell dysfunction, suggesting convergence on common regulatory pathways. Adenosine (ADO), an immunosuppressive purine metabolite generated through extracellular ATP catabolism, has emerged as a context-integrating metabolic checkpoint that regulates immune responses in response to tissue stress and inflammation. Across tumors and HIV, dysregulated ADO signaling reinforces checkpoint pathways and stabilizes dysfunctional CD8+ T cell states. In this review, we examine how the ADO-adenosine deaminase-1 axis shapes CD8+ T cell dysfunction across disease contexts and discuss its potential as a broadly applicable target for immune restoration.

Keywords: ADA-1; CD8+ T cells; T cell dysfunction; adenosine; chronic infection; tumor microenvironment

DOI: https://doi.org/10.1016/j.it.2026.06.005

Front Immunol. 2026 ;17 1743101

The lactylation axis: bridging metabolic reprogramming and immunosuppression in the tumor microenvironment.

Xingxing Tao, Yingjie Liu, Peishan Yu, Wenjiang Wu, Yanli Fu, Ping Lan, Shengzhu Jin.

Protein lactylation, a novel post-translational modification (lysine lactylation, Kla) driven by the oncometabolite lactate, has emerged as a critical epigenetic mechanism that directly links cellular metabolic state to gene regulation. Within the tumor microenvironment (TME), lactate accumulation resulting from the Warburg effect provides abundant substrate for lactylation, positioning this modification as a central hub in cancer biology. This review systematically elucidates the dual role of lactylation in driving tumor progression. Intrinsically, lactylation promotes tumor cell malignancy by globally reshaping chromatin accessibility via histone modifications (e.g., H3K18la) and orchestrating oncogenic signaling pathways through non-histone protein modifications, thereby enhancing metabolic reprogramming, proliferation, invasion, and therapy resistance. Extrinsically, lactylation serves as a key immunosuppressive mechanism by reprogramming the function of immune cells within the TME. It drives macrophages toward an M2-like immunosuppressive phenotype, enhances the suppressive function of regulatory T cells (Tregs), and induces dysfunction and exhaustion in CD8+ T cells, collectively fostering an immune-privileged niche. We further discuss the promising therapeutic strategies targeting the lactylation axis, including inhibitors of lactate production or lactyltransferases, and their combination with immune checkpoint blockade, to reverse immunosuppression and overcome treatment resistance. In summary, understanding the lactylation axis establishes a novel metabolic-epigenetic-immune paradigm and suggests potential new frameworks for precision cancer therapy.

Keywords: cancer immunotherapy; epigenetics; immune evasion; metabolic reprogramming; protein lactylation; tumor microenvironment

DOI: https://doi.org/10.3389/fimmu.2026.1743101

Cancer Immunol Immunother. 2026 Jul 07.

CXCL13-CXCR5 signaling in CD8+ T cell recruitment and lymphoid immune organization in clear cell renal cell carcinoma.

Daniel D Shapiro, Kye D Nichols, Moon Hee Lee, Pavlos Msaouel, Yuanshan Li, Yang Zong, Rong Hu, Wei Huang, Karla Esbona, Toshi Kinoshita, Paz Lotan, Daniel F Roadman, Everlyne Nkadori, Stephanie M McGregor, David J Beebe, Sheena C Kerr, Christian M Capitini, Edwin Jason Abel.

Clear cell renal cell carcinoma (ccRCC) exhibits heterogeneity in immune infiltration and clinical outcomes, but the mechanisms governing recruitment and organization of tumor-reactive CD8+ T cells remain incompletely defined. We investigated the role of the CXCL13-CXCR5 axis in shaping CD8+ T cell recruitment, differentiation, and immune organization in high-risk, non-metastatic ccRCC. Human tumor, plasma, and matched adjacent kidney specimens were analyzed using ELISA, quantitative PCR, migration assays, multiplex immunofluorescence, single-cell RNA sequencing, spatial transcriptomics, and a syngeneic mouse model. CXCL13 was among the most upregulated chemokines in ccRCC relative to matched normal kidney and was embedded within a CD8+ T cell-associated inflammatory transcriptional program. In transwell and microphysiological system (MPS) assays, CXCL13 promoted CD8+ T cell migration, enriched CXCR5+ cells among migrating CD8+ T cells and showed reduced migration after CXCL13 or CXCR5 blockade. Single-cell analyses identified CXCR5 expression within stem-like CD8+ T cell states associated with TCF7 and IL7R, whereas CXCL13 associated with later cytotoxic/exhausted states along a continuous differentiation landscape. Spatial transcriptomics demonstrated that stem-like CD8+ T cells localized within structured lymphoid aggregates enriched for B cells, coordinated CXCL13/CXCR5 expression, and signaling programs. In vivo, tumor-derived CXCL13 suppressed tumor growth, increased intratumoral CD8+ T cell infiltration, and enriched CXCR5+TCF1+CD8+ stem-like T cells. In human tumors, higher CXCL13 expression correlated with increased CXCR5+CD8+ T cell infiltration and improved recurrence-free survival. These findings identify CXCL13 as a regulator of immune recruitment and niche organization and support the CXCL13-CXCR5 axis as a biomarker and possible therapeutic target in ccRCC.

Keywords: CD8 T cell; CXCL13; CXCR5; Chemokine; Immune microenvironment; Kidney cancer; Renal cell carcinoma; Tumor microenvironment

DOI: https://doi.org/10.1007/s00262-026-04489-7