bims-imseme 2026-07-12 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2026–07–12
43 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Engineering T cell metabolism to enhance therapeutic efficacy.
Virtual memory CD8⁺ T cells in aging: heterogeneity, bystander protection, inflammatory potential, and inhibitory regulation.
Adenosine as a metabolic checkpoint in CD8+ T cell dysfunction.
Tumor-driven stabilization of CD8+ T cell exhaustion and implications for cancer immunotherapy.
Mapping self-associating chromatin hubs identifies Id proteins as key determinants of exhausted CD8+ T cell fate.
SIRT5-dependent regulation of ASL controls arginine metabolism and T cell function.
Tissue-resident CD8+ T cells link pregnancy to breast cancer protection.
Differential stem-like potential of naïve and memory CD8 T cells after chronic infection.
Exhausted CD8+ T cell fate is programmed by dynamic CTCF-mediated enhancer activation and invariant CTCF-imposed barriers.
Mitochondrial STAT3-mediated suppression of apoptosis constrains antimycobacterial immunity.
Regulation of T Cell Senescence in Health and Diseases.
Depletion of extracellular asparagine impairs self-reactive T cells and ameliorates autoimmunity in a murine model of multiple sclerosis.
Exhausted CD8+ T cell subsets differ a TAD.
PD-1⁺ CD8⁺ T cells: roles of PD-1 beyond an exhaustion marker.
Sp1 links CD46 to CD4 T cell metabolic fitness, survival, and retroviral control.
Colorectal cancers with distinct metastatic potential trigger divergent early T cell responses.
Apoptotic-Cell Accumulation and Mertk Expression Are Linked to Diminished Antiviral CD8+ T Cell Immunity in Chronic Infections.
Single-cell genomics links targeted functional manipulations to efficacy-associated chromatin signatures in CAR T cells.
Aging reprograms the functional, epigenetic, and metabolic landscape of macrophages.
Constitutive DUSP2 expression enhances lymphoid cell proliferation by activating CDK1 and promotes lymphomagenesis.
TLR9 Agonists Potentiate Adoptive T Cell Therapy in Cancer through a B Cell-CD2 Costimulatory Axis.
Inhibition of Stemness Pathways during Acute SIV Limits Infection of Central Memory CD4+ T Cells and Alters Viral Reservoir Activity in Macaques.
Pertussistoxin as well as Staphylococcal superantigen induce glycolysis as energy source during T cell activation in an adenoid organoid model.
Metabolic Kinases as Regulators of Inter-Organelle Communication in Aging and Age-Related Diseases.
CXCL13-CXCR5 signaling in CD8+ T cell recruitment and lymphoid immune organization in clear cell renal cell carcinoma.
FDA-approved fulvestrant-induced CAR phase separation enables precise control of CAR T antitumor function.
De Novo Designed Minibinders Targeting the GDF15-GFRAL Axis Reverse Cancer Cachexia and Restore Anti-Tumor Immunity.
Sequential infection reprograms the immune landscape to shape future responses.
AMPK-driven immunometabolic reprogramming enhances CD19+CD21hiCD24hi regulatory B cell-mediated suppression of atopic dermatitis.
Enhancing the persistence of therapeutic T cells.
Photosynthetic chlorella-violet phosphorus nanosheet biohybrid alleviating tumor hypoxia for synergistic photodynamic-immunotherapy.
The lactylation axis: bridging metabolic reprogramming and immunosuppression in the tumor microenvironment.
Integrative transcriptomic and proteomic profiling reveals altered thymocyte development and microenvironment remodeling during natural thymic atrophy.
Polyvinyl chloride promotes radioresistance in hepatocellular carcinoma by inhibiting radiotherapy-induced CD8⁺ T cell differentiation.
Dynamic control of nucleotide metabolism in physiology and disease.
Mucosal-associated invariant T cells support IL-15-dependent Treg response in skin injury and promote resolution of skin inflammation.
CART-immune-related adverse events after BCMA CAR-T therapy.
Granzyme K CD8⁺ T cells with tissue-resident features promote intestinal inflammation in patients with Crohn's disease.
Programmable engineered bacteria manipulate metabolism and remodel the TME in situ for enhancing adoptive cell therapy.
Bioinspired 0D mitochondrial bioenergetic actuators rewire cartilage progenitor cell metabolism for osteoarthritis remission.
In vivo engineering tumor cells to a universal "all-in-one" cancer vaccine with full antigen spectrum.
Aging increases ovarian cancer growth, metastasis, and immunosuppression that can be alleviated by inhibiting hedgehog signaling.
Antibiotics promote susceptibility to C. difficile infection through a CCR5-dependent immune response.

Adv Pharmacol. 2026 ;pii: S1054-3589(26)00030-X. [Epub ahead of print]106 117-139

Engineering T cell metabolism to enhance therapeutic efficacy.

Laura Anderson, Nicola J Mason, Roddy S O'Connor.

  Adoptive cell therapies, particularly chimeric antigen receptor (CAR) T cells, function as "living drugs" whose efficacy depends not only on target recognition but also on the metabolic state of the infused product. T cell metabolism governs energy production, redox homeostasis, biomass generation, and adaptation to persistent antigen exposure and nutrient stress, thereby shaping expansion, effector function, persistence, and susceptibility to exhaustion. Core metabolic programs relevant to these outcomes include glycolysis and mitochondrial respiration, anaplerosis and amino acid metabolism, lipid metabolism, and NAD- and redox-linked pathways. These programs help determine adoptive cell therapy-relevant phenotypes, including the balance between immediate cytotoxicity and long-term durability. Increasing evidence further suggests that metabolism can be therapeutically manipulated across the lifecycle of adoptive cell therapy through ex vivo manufacturing, receptor and signaling design, direct gene engineering, and post-infusion support. Collectively, these findings support a pharmacologic framework in which metabolic state is not merely a descriptive correlate of product quality, but a controllable determinant of therapeutic performance. A deeper mechanistic understanding of these pathways may enable more precise strategies to improve persistence, function, and long-term antitumor efficacy.

Keywords:  Adoptive cell therapy; CAR T cells; Ex vivo manufacturing; Metabolic engineering; Metabolic programming; Mitochondrial fitness; T cell exhaustion; T cell metabolism; T cell persistence; Tumor microenvironment

DOI:  https://doi.org/10.1016/bs.apha.2026.05.001
Immun Ageing. 2026 Jul 10.

Virtual memory CD8⁺ T cells in aging: heterogeneity, bystander protection, inflammatory potential, and inhibitory regulation.

Archit Kumar, Raymond Yung.

  Aging reshapes the CD8⁺ T cell compartment through contraction of the naïve pool and expansion of memory-phenotype populations, including the progressive accumulation of antigen-inexperienced virtual memory (VM) CD8⁺ T cells. VM CD8⁺ T cells arise in the absence of foreign antigen priming and acquire a memory-like phenotype. In aged hosts, VM CD8⁺ T cells constitute a substantial fraction of the antigen-inexperienced memory-phenotype CD8⁺ T cell pool, and their differentiation is shaped by self-reactivity, homeostatic cytokines, and transcriptional programs linked to IL-15 and EOMES. During aging, VM CD8⁺ T cells accumulate numerically, display altered proliferative responses, retain sensitivity to homeostatic and inflammatory cytokines, and can preserve effector function during infection. These features suggest that VM CD8⁺ T cells may partially compensate for the age-associated loss of naïve CD8⁺ T cells by providing rapid effector-like responses. At the same time, aged VM CD8⁺ T cells appear to comprise heterogeneous subsets, including populations with cytotoxic and inflammatory potential. Emerging evidence suggests that inhibitory receptors may mark distinct VM states during aging, although their functional significance and potential regulatory role remain to be established.

Keywords:  Aging; CD8+ T cells; Granzymes; Inflammation; Memory T cells; Virtual memory T cells

DOI:  https://doi.org/10.1186/s12979-026-00582-8
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 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
Nat Immunol. 2026 Jul 06.

Mapping self-associating chromatin hubs identifies Id proteins as key determinants of exhausted CD8+ T cell fate.

Wei Hu, Qing Chen, Shaoqi Zhu, Shengen Shawn Hu, Haibo Yu, Vanita Patel, Ying Wang, Vladimir P Badovinac, Yi Zhang, Chongzhi Zang, Weiqun Peng, Hai-Hui Xue.

Within days of exposure to chronic viral infections, activated CD8+ T cells differentiate into Tcf1-Slamf6loTim3hi exhaustion-prone effector T (TEX_EFF) cells or self-renewing Tcf1+Slamf6hiTim3lo precursor exhausted T (TPEX) cells. Here we showed that early CD8+ TEX cell fates were imprinted by forming subset-specific, self-associating chromatin hubs. Chromatin hub assembly coincided with effector or stemness gene induction and identified the transcription cofactors Id2 and Id3 as key regulators that promoted CD8+ TEX_EFF and CD8+ TPEX cell fates, respectively. Id2 drove CD8+ TEX_EFF cell specification by activating effector genes, while suppressing genes involved in exhaustion and stemness. In contrast, Id3-repressed effector genes but upregulated IL-7Rα and AhR, thereby maintaining the CD8+ TPEX cell pool. Mechanistically, Id2 and Id3 exhibited a distinct impact on the chromatin accessibility landscape in early CD8+ TEX cells by engaging Runx3 and Tcf1 transcription factors along with E proteins. These findings indicated that reshaping chromatin architecture represents a critical means for specifying CD8+ TEX cell fates and ensuring lineage stability.

DOI: https://doi.org/10.1038/s41590-026-02578-4
bioRxiv. 2026 Jun 29. pii: 2026.06.24.734337. [Epub ahead of print]

SIRT5-dependent regulation of ASL controls arginine metabolism and T cell function.

Kim Han, Rachael J Klein, Kaiyuan Wu, Anna Chiara Russo, Allison M Meadows, Thomas C Recupero, Rahul Sharma, Anand K Gupta, Nathan T Brandes, Benjamin Schwarz, Michael N Sack.

NAD⁺ supplementation blunts Th1 and Th17 inflammation, in part, through arginine metabolism-dependent regulation of mitochondrial energetics, redox balance and signal transduction. Whether the NAD + -dependent sirtuin deacylases contribute to this regulation is unknown. Here, we show that both SIRT1 and SIRT5 transcript levels are induced in CD4 + T cells in human participants following oral supplementation of the NAD + precursor nicotinamide riboside (NR). Among the sirtuin family members, SIRT5 rather than SIRT1 emerged as the predominant regulator of arginine and fumarate metabolism. Genetic depletion or pharmacologic inhibition of SIRT5 attenuated NR-mediated increases in arginine and fumarate and abolished the anti-inflammatory -effects of NR on Th1 and Th17 cytokine production. In contrast, the responses to exogenous arginine or citrulline supplementation were preserved, indicating that SIRT5 functions upstream of arginine biosynthesis. Metabolomic profiling further demonstrated that SIRT5 is required for NR-induced remodeling of the arginine biosynthetic pathway. Mechanistically, SIRT5 physically interacted with arginosuccinate lyase (ASL), promoted ASL-dependent arginine accumulation, and regulated ASL post-translational acylation, including glutarylation and malonylation. Loss of SIRT5 disrupted NR-mediated redox homeostasis, antioxidant gene expression, and cytokine suppression. Collectively, these findings identify SIRT5 as a critical mediator of NAD⁺ precursor-induced metabolic remodeling that links ASL-dependent arginine metabolism to redox balance and effector function in human CD4⁺ T cells.

DOI: https://doi.org/10.64898/2026.06.24.734337
Nat Immunol. 2026 Jul 07.

Tissue-resident CD8+ T cells link pregnancy to breast cancer protection.

DOI: https://doi.org/10.1038/s41590-026-02580-w
J Immunol. 2026 Jun 07. pii: vkag164. [Epub ahead of print]215(6):

Differential stem-like potential of naïve and memory CD8 T cells after chronic infection.

Kyungmin Lee, Junghwa Lee, Rafi Ahmed, Se Jin Im.

  Memory CD8 T cells respond rapidly upon antigen re-encounter and are considered advantageous for protective immunity. However, they undergo a swift decline under chronic antigen stimulation. In this study, we found that memory CD8 T cells' heightened activation sensitivity promotes terminal differentiation and impairs the formation of CXCR5+Tim-3- progenitor subsets, resulting in reduced persistence. This defect was commonly observed in memory CD8 T cells generated by diverse immunization strategies. Mechanistically, their inability to generate progenitor cells was not due to insufficient expression of TCF1 or TOX upregulation. Importantly, blockade of type I interferon signaling during priming restored progenitor differentiation of secondary activated CD8 T cells. These findings highlight that the activation context of memory CD8 T cells critically influences their fate during persistent infection and suggest that modulating inflammatory signals may enhance the durability of secondary responses.

Keywords:  acute memory CD8 T cells; chronic viral infection; naïve CD8 T cells; progenitor subset

DOI:  https://doi.org/10.1093/jimmun/vkag164
Nat Immunol. 2026 Jul 06.

Exhausted CD8+ T cell fate is programmed by dynamic CTCF-mediated enhancer activation and invariant CTCF-imposed barriers.

Wei Hu, Shaoqi Zhu, Qing Chen, Vladimir P Badovinac, Weiqun Peng, Hai-Hui Xue.

Exhausted CD8+ T (TEX) cells undergo extensive genome reorganization during differentiation, yet the drivers of this process remain elusive. Here we show that CTCF programmed CD8+ TEX cell fates through two distinct modes of action. CTCF acquired de novo binding sites and concordantly induced open chromatin in early CD8+ TEX cells responding to chronic viral infection. The dynamic CTCF binding activated enhancers and promoted chromatin looping. Consequently, genetic ablation of CTCF diminished chromatin accessibility and interaction strength, impairing CD8+ TEX cell proliferation, effector function and bioenergetic mobilization. Conversely, invariant CTCF binding acted as essential chromatin barriers, and loss of CTCF disrupted insulation and caused aberrant chromatin self-association and undue RNA polymerase II pausing, leading to excessive activation of exhaustion- and stemness-linked genes. Thus, CTCF balanced CD8+ TEX cell differentiation by gaining dynamic binding to induce cytotoxicity and sustain metabolic fitness, while its invariant binding compartmentalized exhaustion and stemness program genes to prevent their overexuberant activation.

DOI: https://doi.org/10.1038/s41590-026-02585-5
bioRxiv. 2026 Jul 01. pii: 2026.06.26.734825. [Epub ahead of print]

Mitochondrial STAT3-mediated suppression of apoptosis constrains antimycobacterial immunity.

C J Mabry, A K Coleman, M H Smith, S L Hahn, T M Newbolt, M J Chapman, L W Stranahan, C G Weindel, K L Patrick, R O Watson.

Maintenance of mitochondrial homeostasis is required to balance the host-pathogen interface during Mycobacterium tuberculosis (Mtb) infection. Here, we identify the non-canonical TRIM family member Trim14 as a critical regulator of mitochondrial integrity in Mtb-infected macrophages. Specifically, we demonstrate that Trim14 preserves mitochondrial membrane polarization and limits macrophage apoptosis by controlling phosphorylation and mitochondrial targeting of Stat3. When targeted to mitochondria, Stat3 restricts opening of the mitochondrial permeability transition pore, which raises the macrophage threshold for apoptotic commitment. In vivo , loss of Trim14 enhances apoptosis of macrophages and dendritic cells, leading to augmented antimycobacterial immunity marked by increased CD8 + T cell activation and effector function. Together, these findings define a Trim14-mitochondrial Stat3 axis that suppresses host-protective apoptosis during Mtb infection and pinpoint mitochondrial Stat3 as a potential target for therapies aimed at boosting antimycobacterial immunity.
HIGHLIGHTS: Trim14 raises the apoptotic threshold in Mtb-infected macrophages.Trim14 controls phosphorylation and mitochondrial targeting of Stat3.Reduced mitochondrial Stat3 promotes mPTP opening and apoptotic commitment. Trim14 deficiency enhances apoptosis, CD8 + T cell immunity, and Mtb resistance.

DOI: https://doi.org/10.64898/2026.06.26.734825
Immune Netw. 2026 Jun;26(3): e27

Regulation of T Cell Senescence in Health and Diseases.

Sewon Mun, Seungho Choi, Jaemin Kim, Jihyun Kim, Yeonseok Chung.

  Aging is accompanied by a progressive decline in immune function, a process termed immunosenescence, which affects both innate and adaptive immune compartments. Among these, the adaptive immune system-and particularly T cells-undergoes the most profound functional and phenotypic alterations, critically impairing host defense against infections, cancer, and vaccination responses. The age-associated decline of adaptive immunity is shaped by the divergent senescence pathways of CD4+ helper and CD8+ cytotoxic T cells. While both lineages enter a state of cell-cycle arrest, their distinct immunological roles dictate fundamentally different molecular triggers, metabolic adaptations, and functional outcomes. This review synthesizes these subset-specific differences, highlighting how DNA damage-dependent mechanisms and DNA damage-independent processes drive distinct senescence phenotypes. Furthermore, we discuss how these differences contribute to immune system remodeling during aging and explore emerging therapeutic strategies targeting metabolic and signaling pathways to mitigate T cell senescence.

Keywords:  Aging; Immunosenescence; Metabolic reprogramming; Mitochondrial dysfunction; T cells

DOI:  https://doi.org/10.4110/in.2026.26.e27
Elife. 2026 07 08. pii: RP107745. [Epub ahead of print]14

Depletion of extracellular asparagine impairs self-reactive T cells and ameliorates autoimmunity in a murine model of multiple sclerosis.

Peter Georgiev, Sheila Johnson, Kiran Kurmi, Song-Hua Hu, SeongJun Han, Dillon Patterson, Thao H Nguyen, Linglin Huang, Dan Liang, Naomi Goldman, Thomas Conway, Hannah Creasey, Jared Rowe, Marcia C Haigis, Arlene H Sharpe.

  Amino acids play critical roles in the activation and function of lymphocytes. Here we show that the non-essential amino acid, asparagine, is essential for optimal activation and proliferation of CD4+ T cells. We demonstrate that asparagine depletion at different time points after CD4+ T cell activation reduces mitochondrial membrane potential and function. Furthermore, asparagine depletion at specific time points during CD4+ T cell differentiation reduces cytokine production in multiple CD4+ T cell subsets. In an adoptive transfer model of experimental autoimmune encephalomyelitis (EAE), myelin oligodendrocyte-specific pathogenic T helper 17 cells differentiated under Asn-deficient conditions exhibited reduced encephalitogenic potential and attenuated EAE severity. In a model of EAE induced by active immunization, therapeutic depletion of extracellular Asn significantly reduced disease severity. These results identify asparagine as a key metabolic regulator of the pathogenicity of autoreactive CD4+ T cells and suggest that targeting asparagine metabolism may be a novel therapeutic strategy for autoimmunity.

Keywords:  autoimmune response/disease; immunology; inflammation; lymphocyte subsets; mouse

DOI:  https://doi.org/10.7554/eLife.107745
Nat Immunol. 2026 Jul 06.

Exhausted CD8+ T cell subsets differ a TAD.

Maegan K Murphy, Takeshi Egawa.

DOI: https://doi.org/10.1038/s41590-026-02583-7
Semin Immunopathol. 2026 07 07. pii: 11. [Epub ahead of print]48(1):

PD-1⁺ CD8⁺ T cells: roles of PD-1 beyond an exhaustion marker.

Jingyi Chen, Zixiang Chen, Liangjie Xu, Jieting Jia, Ke Rui, Jie Tian.

  Programmed cell death protein 1 (PD-1) has long been considered a central molecule in CD8⁺ T cell exhaustion and immunosuppression. However, recent studies have revealed that PD-1⁺CD8⁺ T cells are not a homogeneous population of terminally dysfunctional cells, but rather constitute key immune cells with significant heterogeneity and functional plasticity within tissue immune microenvironments. PD-1 signaling operates throughout multiple stages of CD8⁺ T cell biology, including thymic development, peripheral activation, chronic antigen stimulation, and tissue residency. By finely regulating T cell receptors (TCRs) signal strength, metabolic state, and transcriptional programs, it deeply participates in cell fate decisions while limiting immunopathology. In chronic infections and tumors, persistent antigen stimulation drives PD-1⁺CD8⁺ T cells to form an exhaustion lineage with a defined differentiation hierarchy, encompassing stem-like precursor cells, effector-like transitional cells, and terminally exhausted cells. PD-1 is not only a characteristic marker of this lineage but also a critical regulatory node through which immune checkpoint blockade therapy exerts its therapeutic effects. Furthermore, in contexts such as tissue-resident memory T cells (TRM), GZMK⁺CD8⁺ T cells, and other disease-associated microenvironments, sustained PD-1 expression often represents an adaptive functional regulatory state rather than mere functional inhibition. This review explores the multidimensional regulatory roles of PD-1 in CD8⁺ T cells, with a focus on elucidating the diverse functions and clinical significance of PD-1⁺CD8⁺ T cells in cancer, chronic infections, and autoimmune diseases.

Keywords:  CD8⁺ T cell; GZMK; PD-1; PD-1+ CD8+ TRM ; PD-L1; TRM

DOI:  https://doi.org/10.1007/s00281-026-01078-9
Sci Immunol. 2026 Jul 10. 11(121): eaeb5857

Sp1 links CD46 to CD4 T cell metabolic fitness, survival, and retroviral control.

Parul Singh, Luopin Wang, Pavitra Ramdas, Shyaman M Jayasundara, Gaelle Le Friec, Natalia Kunz, Prakriti Mudvari, Erin E West, Ayden Case, Nicolas S Merle, Jack A Bibby, Henrik Hasle, Eli A Boritz, Majid Kazemian, Claudia Kemper.

CD46, a human-specific complement receptor, regulates gene programs essential for T helper 1 (TH1) cell differentiation, yet how it exerts direct transcriptional control remains unclear. We show that the CD46 signaling domain cytoplasmic tail 1 (CYT-1) engages the transcription factor Sp1 in human CD4 T cells to dynamically modulate Sp1-DNA interactions. Beyond promoting TH1 cell induction, CD46-Sp1-controlled programs support naive CD4 T cell survival by maintaining nutrient transporter expression and suppressing the intrinsic caspase 9-caspase 3 apoptotic pathway. The CD46-Sp1 axis also restrains HIV transcription in infected CD4 T cells in vitro. Disruption of CYT-1-Sp1-regulated programs identifies T cells from individuals with HIV who exhibit incomplete viral suppression during antiretroviral therapy. Together, these findings define a human-specific transcriptional mechanism linking complement signaling to metabolic adaptation, apoptosis regulation, and antiviral defense, highlighting an unexpected role for CD46 in coordinating T cell homeostasis and host protection.

DOI: https://doi.org/10.1126/sciimmunol.aeb5857
bioRxiv. 2026 Jul 04. pii: 2026.06.30.735606. [Epub ahead of print]

Colorectal cancers with distinct metastatic potential trigger divergent early T cell responses.

Marwa Saad, Alexandra Thoms, Yue S Yin, Izabela Mamede, Afsana Rahman, Ruonan Chen, Sebastián E Carrasco, Patrick W Darcy, Norihiro Goto, Sohail F Tavazoie, Angelina M Bilate, Daniel Mucida.

Colorectal cancer (CRC) remains a leading cause of cancer mortality, with most cases refractory to immunotherapy. Distinguishing tumor-induced from steady-state mucosal T cell responses has been a critical barrier to understanding antitumor immunity in CRC. Using orthotopic transplantation of CRC organoids with and without metastatic potential, combined with temporal T cell fate-mapping, we show that non-metastatic tumors elicit early recruitment of CD8αβ⁺ and CD4⁺ T cells that acquired cytotoxic and Th1-like programs, whereas pro-metastatic tumors induce a naïve-like, hypoactivated state. Tumor-infiltrating CD4 + T cells underwent clonal expansion, including clones recognizing microbial and dietary antigens. T cells in physical contact with tumor cells, identified by uLIPSTIC, were enriched for expanded and cytotoxic clones. Fate-mapped T cells from non-metastatic tumors suppressed tumor growth in an IFN-γ-dependent manner, whereas pro-metastatic tumor-derived T cells failed to do so. Mechanistically, pro-metastatic tumors downregulated MHCII, and Ciita targeting in non-metastatic organoids reduced CD4⁺ clonal expansion and led to tumor progression. Together, these findings define divergent early T cell trajectories associated with CRC metastatic potential, indicating that ineffective local immune engagement precedes metastatic dissemination.

DOI: https://doi.org/10.64898/2026.06.30.735606
Immune Netw. 2026 Jun;26(3): e26

Apoptotic-Cell Accumulation and Mertk Expression Are Linked to Diminished Antiviral CD8+ T Cell Immunity in Chronic Infections.

Tom Adomati, Thamer A Hamdan, Hilal Bhat, Murtaza Ali, Namir Shaabani, Lamin B Cham.

  Exhaustion of antiviral immunity driven by inhibitory signals is one hallmark of persistent viral infection. Notably, PD-1 and IL-10 are two major contributors to CD8+ T cell dysfunction. How these molecules are specifically induced during chronic viral infection remains mainly unknown. Using the lymphocytic choriomeningitis virus model, we show that the apoptotic-cell accumulation and expression of tyrosine kinase Mertk are linked to the outcome of chronic viral infection. Early CD8+ T cell activation correlated with increased dead-cell deposition, rapid induction of IL-10 and TGF-β in macrophages and dendritic cells (DCs), and a pronounced upregulation of PD-1 on CD8+ T cells and its ligand PD-L1. In TCR-β-deficient mice lacking CD8+ T cells, dead-cell generation and expression of IL-10, TGF-β, PD-1, and PD-L1 were markedly restricted. Our findings suggest that CD8+ T cell-mediated killing of infected targets generates large quantities of apoptotic cells, which activate the phosphatidylserine-binding kinase Mertk on macrophages and DCs. This signalling cascade subsequently promotes expression of IL-10, TGF-β, PD-1, and partially PD-L1. Consistent with this model, loss of Mertk in Mertk-/- mice reduced inhibitory cytokines and PD-1 expression, accelerated antiviral CD8+ T cell responses, and improved viral control. Collectively, our study provides important insight into cellular basis of T cell regulation identifying apoptotic cells and Mertk activation as key mechanisms initiating the suppression of CD8+ T cell immunity during chronic viral infection.

Keywords:  Antigen presenting cells; Apoptosis; CD8-positive T lymphocytes; Immunosuppression; Interleukin; Lymphocytic choriomeningitis virus; MER tyrosine kinase; Programmed cell death protein-1; Suppressors of cytokine signalling; Transforming growth factor

DOI:  https://doi.org/10.4110/in.2026.26.e26
Res Sq. 2026 Jun 29. pii: rs.3.rs-9859689. [Epub ahead of print]

Single-cell genomics links targeted functional manipulations to efficacy-associated chromatin signatures in CAR T cells.

James Scott-Browne, Kole DeGolier, Stephanie DeVoe, Marwan Abushawish, Angela Prete, Terry Fry.

Chimeric antigen receptor (CAR) T cells produce extraordinary remission rates in some hematologic tumors, results inconsistently replicated across malignancies and/or target antigens. Anti-tumor efficacy can be enhanced by modifying CAR architecture or T cell differentiation state. Pooled screening methods to identify effects of modifications are often restricted to in vitro readouts of abundance or transcriptome, limiting ability to interrogate biology and project long-term T cell fates. We use genetically-encoded barcodes to track the effects of diverse functional manipulations on pooled murine and human CAR T cell chromatin states using scATAC-seq. We report stable and transient transcription factor activities programmed by cytokine concentration during in vitro expansion and altered in vivo effector differentiation programs driven by modifications to CAR antigen binding domain construction. These data establish genetic barcoding to tie targeted functional manipulations to single CAR T cell chromatin profiles in vitro and in vivo, providing insights toward augmented therapeutic efficacy.

DOI: https://doi.org/10.21203/rs.3.rs-9859689/v1
Res Sq. 2026 Jun 30. pii: rs.3.rs-10155437. [Epub ahead of print]

Aging reprograms the functional, epigenetic, and metabolic landscape of macrophages.

Manasa Suresh, Francisco Tapia Belmonte, Bryan T Weselman, Xintang Li, Marie Durr, Isabella Duchovny, Yanitza Gutierrez-Monsalve, Matias I Hepp, Satish Kumar R Noonepalle, Alexis Salas-Burgos, Alejandro Villagra.

Immuno-senescence is a dominant risk factor of chronic diseases, yet the impact of aging on macrophages remain understudied, despite their involvement in age-related conditions. Here, we define macrophage aging by integrating transcriptomic, epigenetic, metabolic, and functional analyses across the lifespan. Besides aging hallmarks, we uncovered progressive changes in macrophages, including reduced responsiveness to both inflammatory and anti-inflammatory cues and an imbalanced cytokine and chemokine secretory profile. This age-driven remodeling is supported by significant rewiring of epigenetic regulators, particularly histone-modifying genes, alongside coordinated shifts in metabolism toward lipid activation and trafficking at the expense of mitochondrial redox programs. Strikingly, these alterations differ between M1- and M2-like macrophages, indicating phenotype-specific aging trajectories. Functionally, aged macrophages exhibit enhanced phagocytic capacity, diminished migratory ability, and preserved antigen presentation. Together, our findings establish that aging does not simply impair macrophages; it drives an active, multi-layered reprogramming process, providing a framework to address inflammaging and age-associated diseases.

DOI: https://doi.org/10.21203/rs.3.rs-10155437/v1
Cell Rep. 2026 Jul 10. pii: S2211-1247(26)00730-8. [Epub ahead of print]45(7): 117652

Constitutive DUSP2 expression enhances lymphoid cell proliferation by activating CDK1 and promotes lymphomagenesis.

Yu Qian, Jutatip Panaampon, Bjoern Chapuy, Xueyan Zhang, Xiujuan Zhao, Zhe Wang, Pengfei Zhang, Tongchai Payungwong, Aretina Zhang, Qiang Ke, Jing Zhong, Ping Yuan, Lei Zhang, Min Hong, Il-Kyu Choi, Jiankun Guan, Dinis Pedro Calado, Scott Rodig, Olga Pozdnyakova, Klaus Rajewsky, Susana A Godinho, Siwanon Jirawatnotai, Hao Wu, Margaret A Shipp, Stephanie K Dougan, Baochun Zhang.

  DUSP2 is known as a nuclear dual-specificity phosphatase, highly restricted to immune cells. Its expression is induced by antigenic and mitogenic stimuli and has been implicated in immune cell differentiation and functions. However, its role in immune cell mitotic proliferation and hematologic malignancies has not been rigorously examined. Here, we show DUSP2 is highly expressed in human B-cell, T cell, and other hematologic malignancies. Ablating DUSP2 expression in lymphoma cell lines decreases growth and viability. In mice, transgenic Dusp2 expression promotes B-cell and T cell proliferation, and malignant transformation. Mechanistically, DUSP2 promotes cell cycle progression by activating CDK1 through dephosphorylation at inhibitory Tyr15 and Thr14, which is mediated not by its own phosphatase activity, but instead by a structural motif that recruits CDC25 phosphatases. This work reveals an unexpected oncogenic role for DUSP2 in lymphoid malignancies and the function of a structural motif, which represents an appealing target site for therapeutic intervention.

Keywords:  CDC25; CDK1; CP: Cancer; CP: Immunology; DUSP2, PAC-1; cell cycle; hematologic malignancies; immune cell; lymphomagenesis

DOI:  https://doi.org/10.1016/j.celrep.2026.117652
Cancer Res. 2026 Jul 06.

TLR9 Agonists Potentiate Adoptive T Cell Therapy in Cancer through a B Cell-CD2 Costimulatory Axis.

Ayana T Ruffin, Vasili Toliopoulos, Aubrey S Smith, Soundharya Kumaresan, Megan M Wyatt, Meredith Salzinger, Anna C Cole, Megen C Wittling, Rachel L Mason, James H Carmouche, Mahmoud A Adelbary, Yuan Liu, Avery D Posey, Gregory B Lesinski, Chrystal M Paulos.

Adoptive T cell transfer (ACT) therapy offers curative potential for some patients with cancer. Toll-like receptor (TLR) agonists improve the efficacy of ACT therapy, and elucidating the underlying mechanism of potency could help determine the best way to maximize the benefits of TLR agonists. Here, we identified an innate-adaptive circuit in which TLR9-activated B cells augment CD8+ T cell fitness and antitumor activity through CD2-dependent costimulation. Among multiple TLR agonists tested, class B CpG uniquely programmed murine and human CD8⁺ T cells for superior effector differentiation, metabolic fitness, and antitumor control. Disruption of CD2 signaling blunted the benefits of TLR9 agonism, including impaired glycolytic capacity and reduced tumor control. Independently, blocking other costimulatory molecules, such as CD86, CD80, CD28 or ICOS, did not impair the antitumor activity of CpG-conditioned T cells. Gain of function experiments revealed that CD2 stimulation recapitulated the effect of TLR9 agonism, bolstering the effector function of tumor infiltrating lymphocytes and CAR T cells. Consistent with these findings, elevated CD2 expression in human tumors correlated with improved overall survival across multiple cancer patient cohorts, underscoring the clinical importance of this signaling cue. Together, these data uncover a non-canonical B cell-CD2 costimulation axis through which TLR9 agonists potentiate ACT, revealing a targetable pathway to overcome resistance to cell therapy in solid tumors.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-0202
bioRxiv. 2026 Jul 02. pii: 2026.07.02.734630. [Epub ahead of print]

Inhibition of Stemness Pathways during Acute SIV Limits Infection of Central Memory CD4+ T Cells and Alters Viral Reservoir Activity in Macaques.

Riri Rizkianty Hamid, Inna Ruiz-Salinas, Nils Schoof, Alora Colvin, Sijia Tao, Selwyn J Hurwitz, Alice Lin, Jordan Goldy, Gregory K Tharp, Steven E Bosinger, Raymond F Schinazi, Guido Silvestri, Ann Chahroudi, Maud Mavigner.

The establishment of a reservoir of latently infected CD4+ T cells that persist on antiretroviral therapy (ART) through proliferation represents the main barrier to HIV cure. Here, we evaluated in macaques a therapeutic approach targeting Wnt and Notch pathways that regulate T cell proliferation and differentiation during acute SIV infection, when the viral reservoir is seeded. The combination of PRI-724 and LY3039478 led to reprogramming of central memory CD4+ T cells away from quiescence and stemness toward a metabolically active effector profile resulting in reduced infection of central memory CD4+ T cells. Following sustained ART, levels of SIV RNA in CD4+ T cells were higher in the PRI-724 + LY3039478-treated group compared to controls, although SIV DNA was similar. These findings suggest that stemness pathway inhibition promotes memory T cell differentiation leading to a more transcriptionally active reservoir and has potential to synergize with "shock-and-kill" approaches to reduce HIV persistence.

DOI: https://doi.org/10.64898/2026.07.02.734630
Clin Sci (Lond). 2026 Jul 07. pii: CS20261341. [Epub ahead of print]

Pertussistoxin as well as Staphylococcal superantigen induce glycolysis as energy source during T cell activation in an adenoid organoid model.

Klaus Tenbrock, Christopher T Neullens, Christian Kühne, Renske de Jong, Anandhi Rajendiran, Christoph Kessel, Sabrina B Bennstein, Justus Illgner, Miguel Goncalves, Sebastian P Schraven, Stephan Hackenberg, Dirk Baumjohann, Kim Ohl.

  Bystander activation represents an innate-like mechanism by which T cells, particularly effector and memory subsets, can become activated in the absence of cognate antigen recognition. Using human tonsil organoid cultures as a physiologically relevant model, we investigated bystander activation of CD4+ memory T cells in situ in comparison to superantigen stimulation. Tonsillar T cells were stimulated with pertussis toxin - a component of the childhood pertussis vaccine - in comparison to TSST-1 as the staphylococcal superantigen and assessed for activation status, cytokine expression, RNA expression, and metabolic reprogramming. We observed robust T cell activation and cytokine production as well as transcriptional changes comparable to that elicited by TSST-1. Notably, both bystander- and superantigen-activated T memory cells exhibited a metabolic shift toward glycolysis as the dominant energy pathway. These findings demonstrate the similarities of bystander and superantigen-induced T cell activation and show up pathways to sway bystander activation depending on the immunological context.

Keywords:  Bystander activation; CD4 T cells; Immune organoid; adenoid; immunometabolism

DOI:  https://doi.org/10.1042/CS20261341
Aging Cell. 2026 Jul;25(7): e70624

Metabolic Kinases as Regulators of Inter-Organelle Communication in Aging and Age-Related Diseases.

Md Riad Chowdhury, Jae-Han Jeon, Dipanjan Chanda.

  Cellular aging is accompanied by progressive alterations in metabolic homeostasis, stress adaptation, and organelle function. Increasing evidence suggests that functional coordination among membrane-bound organelles, including mitochondria, the endoplasmic reticulum (ER), lysosomes, peroxisomes, and the Golgi apparatus, contributes to cellular homeostasis during aging. However, the mechanisms linking kinase signaling to specific inter-organelle contact sites or communication pathways remain incompletely defined. In this review, we discuss current evidence linking major metabolic and stress-responsive kinases, including AMPK, pyruvate dehydrogenase kinases (PDKs), mTOR, AKT, and PERK, to organelle coordination in aging and age-related diseases. These kinases regulate mitochondrial dynamics, metabolic flux, calcium and lipid handling, autophagy, lysosomal function, proteostasis, and vesicular trafficking. In some contexts, kinase signaling intersects with defined organelle interfaces, such as mitochondria-associated ER membranes, whereas in many cases the effects on inter-organelle communication are indirect or inferred from broader changes in organelle function. We further discuss how kinase dysregulation may contribute to age-associated defects in mitochondria-ER, mitochondria-lysosome, mitochondria-peroxisome, and ER-Golgi coordination in neurodegeneration, cardiometabolic disease, cellular senescence, and inflammaging. By distinguishing direct contact-site regulation from indirect functional coordination, this review highlights kinase-regulated organelle communication as an emerging, but still incompletely resolved, framework for understanding cellular decline during aging.

Keywords:  age‐related diseases; aging; inter‐organelle communication; metabolic kinases; mitochondrial quality control

DOI:  https://doi.org/10.1111/acel.70624
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
Cell Stem Cell. 2026 Jul 10. pii: S1934-5909(26)00232-8. [Epub ahead of print]

FDA-approved fulvestrant-induced CAR phase separation enables precise control of CAR T antitumor function.

Yuwei Huang, Qichen Zhang, Kun Wang, Xiaohua Ren, Hao He, Jinjiao Wang, Li Li, Zhichao Tan, Jiayong Liu, Guangya Zhu, Haopeng Wang.

  Chimeric antigen receptor (CAR) T cell therapy faces challenges, such as tumor relapse due to antigen loss and poor CAR T cell expansion in vivo. Optimal tonic signaling (spontaneous CAR signaling) is crucial for CAR T cell fitness and antitumor function, requiring precise calibration to avoid dysfunction or exhaustion. Although CAR phase separation can enhance CAR clustering and tonic signaling to improve cytotoxicity and antigen sensitivity, constitutively high signaling could lead to potential side effects, including cytokine storm and neuronal toxicity. To overcome this limitation, we developed a drug-inducible phase-separation CAR (iPhase-CAR) system utilizing FDA-approved fulvestrant and an engineered estrogen receptor α (ERα) mutant as the drug-inducible phase-separation (DiPS) module. Incorporating the DiPS module into CARs enables drug-inducible clustering of CARs on T cell membranes. iPhase-CAR T cells demonstrate superior antitumor function. This system provides quantitative, reversible promotion of CAR T effector functions, enabling precise control over therapeutic efficacy only upon administration of the FDA-approved drug.

Keywords:  CAR T cell therapy; fulvestrant; liquid-liquid phase separation; tonic signaling

DOI:  https://doi.org/10.1016/j.stem.2026.06.005
Adv Sci (Weinh). 2026 Jul 07. e76202

De Novo Designed Minibinders Targeting the GDF15-GFRAL Axis Reverse Cancer Cachexia and Restore Anti-Tumor Immunity.

Haitao Wang, Tianzhen Hua, Meiling Wang, Bingbing Meng, Yue Zhang, Chengxu Jiang, Yunhe Gao, Hongqi Yang, Jian Bo.

  Cancer-associated cachexia is a devastating syndrome characterized by progressive weight loss, reduced survival, and impaired responses to anticancer therapies. Growth differentiation factor 15 (GDF15), acting through its receptor GFRAL, has emerged as a key mediator of cachexia, yet effective and mechanistically defined strategies to neutralize this pathway remain limited. Here, we applied structure-guided de novo protein design to generate compact minibinders that selectively target the GDF15-GFRAL interaction interface. Using an integrated computational pipeline combining RFdiffusion, ProteinMPNN, and AlphaFold 3 structure prediction, we designed and experimentally validated high-affinity GDF15 minibinders with picomolar-range binding affinities and exceptional structural stability. Mutagenesis and charge-complementary rescue experiments confirm that these minibinders neutralize GDF15 through precisely engineered interface contacts. Functionally, the minibinders suppress GDF15-GFRAL signaling, inhibit downstream transcriptional responses, and robustly reverse cachexia in vivo across multiple tumor models, resulting in significant improvements in body weight and survival. Importantly, neutralization of GDF15 also restores sensitivity to anti-PD-1 immunotherapy in a GDF15-driven resistant tumor model. Combination treatment enhances CD8+ T cell infiltration and effector function within tumors, and its antitumor efficacy is strictly dependent on CD8+ T cells. Together, these findings demonstrate that de novo designed GDF15 minibinders can achieve potent, mechanism-defined neutralization of the GDF15-GFRAL axis in vivo, translating into robust physiological benefits and restoration of immunotherapy efficacy.

Keywords:  GDF15; RFdiffusion; cancer cachexia; de novo protein design; immune checkpoint blockade

DOI:  https://doi.org/10.1002/advs.76202
bioRxiv. 2026 Jul 01. pii: 2026.06.26.734836. [Epub ahead of print]

Sequential infection reprograms the immune landscape to shape future responses.

Mengdi Guo, Yanis Hichem Bouzaher, Diala Abd-Rabbo, Rene Quevedo, Heidi J Elsaesser, Wenxi Xu, Melissa Yi Ran Liu, Fauzia N Izzati, M Teresa Ciudad, Matthew Bianca, Zhe Qi Liu, Joao E M de Oliveira, Arthur Mortha, Landon J Edgar, Tracy L McGaha, Tiffany A Reese, David G Brooks.

Mouse models have been instrumental in defining immune mechanisms but often fail to capture the complexity of human immunity, limiting clinical translation. A major limitation is the immunological immaturity of specific pathogen-free (SPF) mice relative to pathogen-experienced adult humans. Here, we use a sequential infection (SI) model that recapitulates cumulative pathogen exposure and define its impact on immune composition and function. Beyond the previously reported expansion of memory T cells, SI induced durable, system-wide remodeling across lymphoid and non-lymphoid tissues, reshaping innate and adaptive immune populations, tissue-resident immunity, and hematopoietic output. Single-cell transcriptomic analyses revealed inflammatory imprinting of naïve CD4 and CD8 T cells, whereas memory T cells acquired enhanced effector programs coupled with reduced biosynthetic activity, transcriptional states that more closely resemble those of pathogen-experienced adult humans. Functionally, SI mice recapitulated the human response to anti-CD28 super-agonist and exhibited altered magnitude and differentiation of acute and chronic antiviral T cell responses, demonstrating that cumulative pathogen exposure reshapes both existing immunity and the generation of future immune responses. Thus, cumulative pathogen exposure coordinately remodels hematopoiesis and naïve and memory lymphocyte states, establishing a durable inflammation-experienced immune landscape that reshapes both immune memory and future immune responses, with broad implications for the translational fidelity of preclinical mouse models.

DOI: https://doi.org/10.64898/2026.06.26.734836
J Allergy Clin Immunol. 2026 Jul 07. pii: S0091-6749(26)00480-X. [Epub ahead of print]

AMPK-driven immunometabolic reprogramming enhances CD19+CD21hiCD24hi regulatory B cell-mediated suppression of atopic dermatitis.

Seung Taek Lee, Ha Eun Kim, So-Yeon Kim, Jong Yeong Lee, Kyung-Hwa Nam, Sang-Hyun Kim, Jun-Young Park, Jin Kyeong Choi.

   BACKGROUND: Atopic dermatitis (AD) is characterized by dysregulated immune responses and persistent inflammation. Regulatory B cells (Bregs) suppress inflammation, but the metabolic mechanisms constraining their function in AD remain unclear.
OBJECTIVE: We sought to define whether immunometabolic regulation governs Breg differentiation and function in AD.
METHODS: Mouse and human B cells were stimulated with the AMPK activator AICAR under inflammatory conditions, with genetic and pharmacologic perturbations. Functional and mechanistic analyses were performed using co-culture systems, a 2,4-dinitrochlorobenzene (DNCB) and Dermatophagoides farinae extract (DFE)-induced murine model of AD, adoptive transfer approaches, adoptive transfer, and human PBMCs from patients with AD.
RESULTS: AICAR treatment or adoptive transfer of AICAR-induced Bregs significantly attenuated AD-like inflammation, whereas AMPK inhibition or IL-10 blockade abrogated these effects. Mechanistically, AICAR induced IL-10-producing Bregs through AMPK-dependent suppression of mTOR signaling and mitochondrial reactive oxygen species while preserving oxidative phosphorylation. This reprogramming selectively enhanced regulatory B cell function and suppressed STAT1 signaling without affecting STAT3. Functionally, these Bregs suppressed Th1, Th2, and Th17 responses in an IL-10-dependent manner without expanding Foxp3+ regulatory T cells. In human PBMCs from patients with AD, AICAR restored immunometabolic coupling by increasing IL-10-producing B cells and reducing pro-inflammatory cytokine production.
CONCLUSION: These findings identify an AMPK-mTOR-redox metabolic checkpoint that governs regulatory B cell function and restrains AD inflammation, linking metabolic control to immune regulation.

Keywords:  AMPK; Atopic dermatitis; B cell regulation; IL-10; Immunometabolism; Inflammation; Metabolic reprogramming; Mitochondrial reactive oxygen species; Regulatory B cells; mTOR

DOI:  https://doi.org/10.1016/j.jaci.2026.06.015
Adv Pharmacol. 2026 ;pii: S1054-3589(26)00037-2. [Epub ahead of print]106 101-116

Enhancing the persistence of therapeutic T cells.

Gregory M Chen, Joseph A Fraietta.

  Therapeutic T cells show enormous promise for the treatment of cancer and other diseases, and an intriguing attribute of T cells for cellular therapy is their ability to have persist and perform cytotoxic function for years. With the advances in T-cell therapies such as CAR T-cell therapy for cancer, long-persisting therapeutic T cells have now been studied in clinical settings and revealed unexpected T-cell poulations. Based on these studies, an emerging framework of long-lived cytotoxic T cells may guide the rational design of new therapies optimized for long-lasting efficacy. The ideal duration of therapeutic T-cell persistence varies by clinical context, and the design of T-cell therapies should follow the therapeutic objective. This chapter highlights the central objective of enhancing the persistence of therapeutic T cells in various clinical contexts, and discusses the ways in which our growing knowledge of long-persisting T cells can guide the next generation of cell therapies.

Keywords:  CAR T-cell therapy; Cancer immunotherapy; T-cell persistence; T-cell therapy

DOI:  https://doi.org/10.1016/bs.apha.2026.05.008
Biomater Adv. 2026 Jul 06. pii: S2772-9508(26)00357-2. [Epub ahead of print]188 215059

Photosynthetic chlorella-violet phosphorus nanosheet biohybrid alleviating tumor hypoxia for synergistic photodynamic-immunotherapy.

Yuwei Fan, A M Omer, Xiao-Kun Ouyang, Nan Wang.

  Tumor metabolic reprogramming, typified by the Warburg effect, promotes hypoxia and immunosuppression in the tumor microenvironment (TME), thereby limiting therapeutic efficacy. Herein, we report a photosynthetic Chlorella (Chl)-violet phosphorus nanosheets (VP) biohybrid system (Chl@VP) for synergistic O2 supply, metabolic perturbation, and photodynamic therapy (PDT)-enhanced tumor treatment. In this system, Chl continuously generates O2 under irradiation to alleviate hypoxia, while VP produce reactive oxygen species (ROS) and release phosphate species for metabolic modulation. Chl@VP significantly enhances ROS generation, induces mitochondrial damage, elevates intracellular phosphate levels, and reduces lactate production, suggesting disruption of the glycolysis-dominant metabolic state of tumor cells. In vivo, Chl@VP combined with laser irradiation exhibits potent tumor suppression and reduced HIF-1α expression, indicating effective hypoxia relief. Moreover, Chl@VP has been demonstrated to promote dendritic cell maturation, thereby enhancing CD8+ T cell activation and tumor penetration, and decreasing regulatory T-cell populations, demonstrating effective immune microenvironment remodeling. Overall, Chl@VP achieves amplified antitumor efficacy through the synergistic integration of hypoxia alleviation, phosphate-mediated metabolic intervention, and ROS-amplified oxidative stress, providing a bioinspired strategy for combining metabolic regulation with PDT for cancer therapy.

Keywords:  Heterojunction; Immunotherapy; Photodynamic therapy; Photosynthetic chlorella; Tumor hypoxia; Violet phosphorus nanosheet

DOI:  https://doi.org/10.1016/j.bioadv.2026.215059
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
Front Cell Dev Biol. 2026 ;14 1816627

Integrative transcriptomic and proteomic profiling reveals altered thymocyte development and microenvironment remodeling during natural thymic atrophy.

Wei Lin, Fuju Sun, Haitao Pan, Jiali Yao, Mengyao Wang, Kang Ye, Jing Yang.

   Background: Age-related thymic atrophy (ARTA) is a hallmark of immunosenescence, yet the earliest thymocyte developmental checkpoints affected by increasing age and the coordinated molecular programs that drive thymic degeneration remain incompletely defined.
Methods: We compared young (1-month-old) and middle-aged (MA, 12-month-old) male ICR mice using thymus weight/index measurement, histopathology, peripheral blood cell analysis, and immunostaining of thymic markers. We further performed RNA-seq and data-dependent acquisition (DDA) proteomics, followed by integrated transcriptomic-proteomic pathway analyses. Finally, we analyzed public human thymus datasets to assess the translational relevance of our findings.
Results: Middle-aged mice exhibited marked thymic involution with reduced thymus weight and thymic index, accompanied by peripheral lymphopenia and reduced peripheral T-cell counts, while myeloid populations (neutrophils and monocytes) increased. Pathological examination revealed lipid droplet accumulation in the thymus of aged mice, along with decreased Ki-67 expression and an increased number of apoptotic cells. Histologically, aged thymuses showed cortical thinning and an indistinct corticomedullary boundary. Reduced cortical CD25 with increased CD44 is suggestive of a possible developmental impediment around the DN1-to-DN2 transition; in parallel, CD3+, CD4+, and CD8+ T cells were reduced in MA mice. Transcriptomics identified broad remodeling (2,084 upregulated and 255 downregulated genes), featuring heightened inflammatory responses, extracellular matrix (ECM)-receptor interaction, and fatty acid metabolism, with suppression of DNA replication-related programs. Proteomics revealed concordant shifts (189 upregulated and 91 downregulated proteins), including enhanced metabolic and ECM-related pathways and reduced DNA replication and T-cell differentiation signatures. Integrated multi-omics highlighted 289 synchronously upregulated gene-protein pairs enriched in focal adhesion, PI3K/Akt signaling, ECM-receptor interaction, and complement/coagulation cascades, indicating coordinated microenvironmental injury and remodeling during thymic atrophy. In the translational relevance analysis, the aging human thymus exhibited features similar to those observed in mice, including impaired DNA replication, increased ECM-receptor interaction, and enhanced fatty acid metabolism-related activity, with thymic stromal cell analysis indicating that these processes are closely associated with mesenchymal cells.
Conclusion: Increasing age disrupts early thymocyte differentiation and is accompanied by inflammatory-ECM remodeling and adipose-associated metabolic reprogramming. These integrative omics signatures nominate candidate pathways and regulators for developing interventions to mitigate ARTA and preserve immune homeostasis.

Keywords:  immunosenescence; proteomics; thymic atrophy; thymocyte development; transcriptomics

DOI:  https://doi.org/10.3389/fcell.2026.1816627
Nat Commun. 2026 Jul 10.

Polyvinyl chloride promotes radioresistance in hepatocellular carcinoma by inhibiting radiotherapy-induced CD8⁺ T cell differentiation.

Haibo Zhang, Yanwei Lu, Hao Xiong, Lei Shi, Hongen Xu, Yongshi Jia, Jun Zhao, Hailong Sheng.

Radiotherapy is standard-of-care treatment for intermediate and advanced hepatocellular carcinoma (HCC); however, resistance remains widespread. Microplastics are detectable in various tumors and may disrupt immune responses, but evidence regarding the role of microplastics in radiotherapy is scarce. Here we show that various types of microplastics are detectable in 52 of the 72 HCC samples we examine, but only polyvinyl chloride (PVC) impairs radiotherapy efficacy. Mechanistically, irradiation enhances histone lactylation, which promotes transcription of HMG-CoA reductase in HCC cells, thereby facilitating cholesterol synthesis and reinforcing CD8+ T cell stemness. PVC alters cholesterol localization and affects CD8⁺ T cell differentiation, which results in the maintenance of an immunologically cold tumor immune microenvironment. A high-cholesterol diet restores CD8+ T-cell stemness and improves therapeutic response to radiotherapy in PVC-infiltrated HCC. Targeting cholesterol metabolism may represent a potential combinatorial strategy to enhance the efficacy of radiotherapy in PVC-infiltrated HCC.

DOI: https://doi.org/10.1038/s41467-026-75415-9
Nat Cell Biol. 2026 Jul 08.

Dynamic control of nucleotide metabolism in physiology and disease.

Dohun Kim, Gerta Hoxhaj.

Nucleotides are essential for life, serving not only as the building blocks of the genome but also as cellular energy providers, metabolic cofactors and signalling molecules. To sustain cellular function and proliferation, cells must continuously generate, recycle and precisely balance nucleotide pools in response to fluctuating metabolic and environmental demands. Nucleotide metabolism is therefore not a static biosynthetic pathway, but a dynamic system tightly integrated with cell signalling and physiology. Here we highlight the regulatory logic of nucleotide metabolism, from acute post-translational regulation to transcriptional scaling, feedback control and higher-order spatial organization into multi-enzyme assemblies and filaments. Through the lens of human genetic disorders and cancer, we examine how nucleotide depletion, pool imbalance or intermediate toxicity produce striking tissue-selective pathologies. Together, these principles position nucleotide metabolism as a central regulatory axis linking cellular metabolism, signalling and fate in health and disease.

DOI: https://doi.org/10.1038/s41556-026-02004-9
bioRxiv. 2026 Jul 01. pii: 2026.06.28.735088. [Epub ahead of print]

Mucosal-associated invariant T cells support IL-15-dependent Treg response in skin injury and promote resolution of skin inflammation.

Grace E Crossland, Andre Armero, Vianey Chavez, Zachary T Peters, Lennard Ostendorf, Shriya Kannan, Lindsay K Mendyka, Olivia F Brooker, Kaitlyn Dowling, Himanshu B Goswami, Dorothea Barton, Sonia Leach, Fred W Kolling, Pamela C Rosato, Mark S Sundrud, Theresa T Lu, Deepak A Rao, Michael G Constantinides, Sladjana Skopelja-Gardner.

Mucosal-associated invariant T (MAIT) cells are enriched at barrier sites, but their role in autoimmune skin inflammation remains unknown. Using cutaneous lupus as a model, we identify MAIT cells as protective regulators of skin inflammation and as critical upstream modulators of regulatory T cells (Treg). Topical MAIT cell activation with 5-OP-RU induced durable resolution of spontaneous skin lesions in MRL/lpr mice and suppressed TLR7-driven skin inflammation. MAIT cell activation selectively expanded and activated Treg populations in both healthy and lupus-like skin, while suppressing effector T cell cytokine production and cytotoxic programs. This MAIT-Treg axis was also activated in UV light-driven barrier injury in healthy murine and human skin, where MAIT cells were required for UV-elicited Treg expansion and function. In lupus-like skin, local MAIT cell activation restored the defective UVB-induced Treg response and limited CD8+ T cell expansion. Mechanistically, CCR2+ monocyte-derived antigen-presenting cells and IL-15 signaling were required for MAIT cell-driven Treg accumulation and therapeutic benefits of MAIT cells in inflamed skin. These studies identify a MAIT-IL-15-Treg axis that links barrier injury sensing to immune regulation, which is disrupted in cutaneous lupus, and nominate therapeutic MAIT cell activation as an unappreciated strategy for restoring immune homeostasis in inflamed skin.

DOI: https://doi.org/10.64898/2026.06.28.735088
Mol Ther Oncol. 2026 Sep 17. 34(3): 201274

CART-immune-related adverse events after BCMA CAR-T therapy.

Luca Paruzzo, Matthew Ho, Julia Han Noll, Alfred L Garfall, Adam D Cohen, Joseph A Fraietta, Marco Ruella.

DOI: https://doi.org/10.1016/j.omton.2026.201274
Exp Mol Med. 2026 Jul 06.

Granzyme K CD8⁺ T cells with tissue-resident features promote intestinal inflammation in patients with Crohn's disease.

Yoonho Lee, Tae-Young Kim, Yongjae Kim, Jiwon Baek, Hwan Park, Do Kyung Yoon, Sung Wook Hwang, Jong Lyul Lee, Sang Hyoung Park, Jihun Kim, Suk-Kyun Yang, Buhm Han, Mi-Na Kweon, Kyuyoung Song, Yong Sik Yoon, Byong Duk Ye, Ho-Su Lee.

The role of CD8+ T cells in Crohn's disease (CD) pathogenesis remains incompletely understood. This study aimed to characterize CD8+ T cells in CD and elucidate their potential contribution to intestinal inflammation. T cells from blood and intestinal tissues of 15 patients with CD were analyzed using single-cell RNA and T cell receptor sequencing. Spatial transcriptomics was conducted on inflamed intestinal tissues from two patients. Analysis of 41,699 CD8+ T cells identified distinct subsets characterized by differential granzyme expression: granzyme B (GZMB+) CD8+ T cells, predominantly in blood with high cytotoxic potential, and granzyme K (GZMK+) CD8+ T cells, enriched in intestinal tissue with lower cytotoxic potential. In the small intestine, GZMK+CD8+ T cells displayed enhanced tissue residency signatures (for example, CXCR6) and downregulated egress-related genes (S1PR1and S1PR5). GZMK+CD8+ T cells displayed robust interactions with myeloid cells via the CXCR3-CXCL9/10 axis, coupled with notable colocalization in the small intestine. Pharmacological inhibition of GZMK alleviated intestinal inflammation and tissue damage in a murine model of intestinal injury, supporting its role in modulating inflammatory responses. Together, these findings highlight GZMK as a potential modulator of intestinal inflammation and a candidate for further therapeutic investigation.

DOI: https://doi.org/10.1038/s12276-026-01763-7
Mol Ther. 2026 Jul 09. pii: S1525-0016(26)00568-X. [Epub ahead of print]

Programmable engineered bacteria manipulate metabolism and remodel the TME in situ for enhancing adoptive cell therapy.

Jin Chen, Tianliang Liu, Xiumin Liu, Hongyue Zhang, Chen Wang, Yuan Meng, Miaoqing Wu, Sachiyo Nomura, Zhe Zhang, Songcheng Yin, Changhua Zhang, Aoran Dong.

In solid tumors, the efficacy of adoptive T cell therapy (ACT) is limited by a metabolically constrained tumor environment that undermines T-cell persistence, fitness and infiltration. Here we engineered a hypoxia-activated bacterial hybrid system (MM@TMV) to address these barriers. This hybrid system integrates metabolically engineered bacteria and tumor membrane vesicles (TMVs) to achieve tumor-restricted metabolic reprogramming and immune reinforcement within hypoxic tumors. Within hypoxic tumors, D-mannose is produced in situ to support stem-like phenotypes and limit exhaustion, while TMVs facilitate both direct and APC-mediated activation of CAR-T and TCR-T cells, concurrently restraining tumor cell growth. In orthotopic, refractory, and metastatic tumor models, MM@TMV further improved T cell persistence, enhanced intratumoral infiltration, and achieved sustained tumor suppression. In a humanized patient-derived xenograft model of Claudin18.2-positive gastric tumors, MM@TMV similarly potentiated clinically relevant ACT. Biosafety tests confirmed systemic safety. Collectively, our findings establish engineered bacteria as programmable immune metabolic modulators that enable effective and safe ACT in solid tumors.

DOI: https://doi.org/10.1016/j.ymthe.2026.06.042
Bioact Mater. 2026 Dec;66 193-220

Bioinspired 0D mitochondrial bioenergetic actuators rewire cartilage progenitor cell metabolism for osteoarthritis remission.

Weiming Lin, Zehao Chen, Wencai Liu, Xin Wang, Wei Song, Axiang He, Yanjie Mao, Han Guo, Zheng Jiang, Chao Zhou, Yuhao Yu, Wanjun Liu.

  Mitochondrial dysfunction and consequent bioenergetic collapse in cartilage progenitor cells (CPCs), driven by excessive mitochondrial reactive oxygen species (ROS), constitute a fundamental barrier to endogenous cartilage regeneration and accelerate osteoarthritis (OA) progression. Accordingly, precise modulation of mitochondrial ROS is required to restore mitochondrial metabolic homeostasis. However, conventional antioxidant agents such as N-acetylcysteine (NAC) lack cell specificity and organelle-level precision, and exhibit limited bioavailability, thereby restricting their capacity to effectively reestablish mitochondrial metabolic homeostasis. Here, we engineer zero-dimensional (0D) bioinspired nanoassemblies, CPC membrane-coated (3-carboxypropyl)triphenylphosphonium bromide-functionalized NAC-derived carbon quantum dots (CM@TQDs), with capabilities for homotypic recognition and mitochondria-targeted metabolic reprogramming. Subsequently, CM@TQDs are encapsulated within ROS/pH-responsive hydrogel microspheres (HGCT), permitting inflammation-triggered release within the OA joint. Upon HGCT-mediated delivery and cellular internalization, the 0D nanoassemblies accumulate in mitochondria in a membrane potential-dependent manner, enhancing local mitochondrial bioavailability. Mechanistically, HGCT effectively scavenges mitochondrial ROS, restores oxidative phosphorylation, reestablishes tricarboxylic acid cycle flux, and suppresses aberrant glycolytic dependence. This metabolic restoration reactivates PI3K/AKT signaling, mitigates apoptosis and ferroptosis, and promotes CPC proliferation and chondrogenic differentiation. In vivo, HGCT attenuates synovial inflammation and enhances cartilage regeneration, markedly inhibiting OA progression. Collectively, this work establishes a nanobiomimetic therapeutic platform capable of achieving hierarchical precision from cell-specific targeting to organelle-level metabolic regulation, offering a promising strategy for nanoscale bioenergetic intervention in degenerative diseases.

Keywords:  Cartilage progenitor cell; Cartilage regeneration; Cell membrane coating; Energy metabolism; Quantum dots

DOI:  https://doi.org/10.1016/j.bioactmat.2026.06.045
Sci Adv. 2026 Jul 10. 12(28): eaee5201

In vivo engineering tumor cells to a universal "all-in-one" cancer vaccine with full antigen spectrum.

Wanting Wang, Yue Huang, Junshi Zhang, Yuan Wang, Zekun Yu, Fanmeng Zhang, Huihui Zhang, Ruiqi Zhang, Runbo Zhong, Hua Zhong, Lu Zhang, Chen Liu, Chenchen Shen, Zhaoyu Li, Mei Wang, Xuanming Yang.

Cancer vaccines offer a promising strategy to initiate de novo T cell responses or enhance existing ones, either functioning independently or synergizing with T cell-modulating therapeutics to reduce tumor burden. The clinical development of cancer vaccines faces challenges such as limited antigen coverage, insufficient antigen presentation, immune suppressive microenvironment, and the availability of personalized vaccines. In this study, we developed a universal "all-in-one" cancer cell-derived vaccine (UniCVac) with comprehensive antigen spectrum coverage by programming tumor cells into antigen-presenting cells (APCs) through the codelivery of CIITA, NLRC5, CD80, and IL-2. This reprogramming mimics the professional APC phenotype, providing simultaneous HLA-I and HLA-II antigen presentation, costimulation, and T cell proliferation signals. These tumor-derived UniCVac can directly activate both CD4+ and CD8+ T cells in vitro, independent of APCs. In addition, their costimulation and T cell growth-stimulating capabilities result in superior CD4+ and CD8+ T cell activation and proliferation comparable to traditional APCs, with enhanced PI3K-AKT pathways activation. Single-cell transcriptome analysis confirmed the similarity in cellular subtypes between UniCVac-activated and traditional APC-activated T cells. In mouse models, the UniCVac vaccination reprogramed the tumor microenvironment from immunosuppressive to immune-permissive, induced robust CD4+ and CD8+ T cell expansion in both preventive and therapeutic tumor models, and achieved complete tumor regression in vivo. Our approach provides a platform for the development of universal cancer vaccines with full antigen spectrum coverage and the ability to directly activate both CD4+ and CD8+ T cells, offering potential combinatorial opportunities with existing T cell-based immunotherapies against cancer.

DOI: https://doi.org/10.1126/sciadv.aee5201
bioRxiv. 2026 Jul 01. pii: 2025.12.23.695206. [Epub ahead of print]

Aging increases ovarian cancer growth, metastasis, and immunosuppression that can be alleviated by inhibiting hedgehog signaling.

Asha Kumari, Mohamed Halaby Elbahoty, Resha Rajkarnikar, Khushi Sureja, Manan Virendra Nayyar, Mehri Monavarian, Liz Macias Quintero, Katherine Fuh, Daniel J Tyrrell, Lalita A Shevde, Sudarshan Anand, Camilla Margaroli, Karthikeyan Mythreye.

Ovarian cancer incidence and mortality increase with age, yet how aging shapes tumor progression and the immune microenvironment remains poorly defined. Using orthotopic syngeneic models of distinct cellular origins (ovarian surface epithelial and fallopian tube-derived) in young versus aged mice, we show that aged hosts exhibit higher tumor burden, metastasis and ascites. Follicle depletion in young mice did not recapitulate these effects, indicating contributions beyond hormonal decline. Spatial transcriptomics revealed distinct age dependent intratumoral heterogeneity, with Hedgehog signaling enrichment in CD45 + cells from aged tumors, alongside elevated CD206 + tumor-associated macrophages and FoxP3 + regulatory T cells. Pharmacologic Hedgehog inhibition in aged mice suppressed tumor growth, reduced metastasis, and decreased CD206 + macrophages and FoxP3 + T cells while preserving CD8 + T cells. In human ovarian cancer, Hedgehog activation correlated with immunosuppressive and immune checkpoint resistance signatures. We propose Hedgehog inhibition as an immunomodulatory strategy for Hedgehog activated or post menopausal ovarian cancer.

DOI: https://doi.org/10.64898/2025.12.23.695206
bioRxiv. 2026 Jun 29. pii: 2026.06.24.734321. [Epub ahead of print]

Antibiotics promote susceptibility to C. difficile infection through a CCR5-dependent immune response.

Md Jashim Uddin, Nick R Natale, Farha Naz, Jiayi Tian, Rachel McMillan, Duncan J Hart, Shelby L Schenck, William A Petri.

Antibiotics (ABXs) represent the current standard of care for treating Clostridioides difficile infection (CDI). Paradoxically, ABX-induced dysbiosis is the primary risk factor for CDI, as disruption of the colonic microbial ecosystem creates an opportunity for C. difficile colonization. Given that ABXs can also alter immune responses, we investigated whether ABXs prime the colonic immune milieu for CDI susceptibility. Here, we implicate ABXs in driving CDI severity through the emergence of pathogenic CCR5-reliant immune populations in the mouse colon. High-throughput immune cell profiling revealed that ABXs shift the colonic immune compartment toward a CCR5-associated type I immunity signature, marked by an expansion of CCR5 + ILC1s and CCR5 + Th1 cells. A partial genetic deletion of CCR5 reversed CDI severity, alleviating colonic inflammation and improving survival. Pharmacological inhibition of the CCL3/4/5-CCR5 circuit also recapitulated these favorable disease outcomes, which we attribute to reduced colonic CCR5 + ILC1, CCR5 + Th1, and CCR5 + CD8 T cell populations during CDI. Together, our findings extend beyond dysbiosis as the canonical CDI risk factor and establish ABX-induced immune imbalance as an underappreciated determinant of CDI susceptibility.

DOI: https://doi.org/10.64898/2026.06.24.734321