Olga Payar @Olgapaval

Nature research paper: PLA2G2D in tumour-draining lymph nodes regulates anti-tumour immunity go.nature.com/4dypGzg

A stress-adaptive lipid kinase axis defines metabolic vulnerabilities in neuroendocrine prostate cancer dlvr.it/TVTbFY

Cyclic Peptide PROTACs Restore VHL-Mediated HIF-1α Degradation in Hypoxia pubs.acs.org/jacsat/article…

Un tumor envío señales nerviosas por vía simpática para reprogramar a un grupo de células (macrófagos alveolares) para que frenen a los linfocitos T que lo estan atacando. Este fue un hallazgo de un grupo de investigadores de adenocarcinoma de pulmón en modelo ratón publicado en febrero 2026.

MAP17 drives a novel SGLT2–glycolysis axis that fuels trained immunity and accelerates atherosclerosis under hyperglycemia. Targeting MAP17 may break the metabolic–inflammatory loop in diabetic vascular disease ahajrnls.org/4AdIwp1

#WCLC26 🌟First report of a combination of a #bispecific targeting PDL1 x VEGF (pumitamig) plus a B7-H3.l ( Elfie-D) #ADC in ES-SCLC, producing excellent responses in all lines of treatment and especially 1L with tolerable toxicity profile. Requires longer follow up to evaluate long-term tolerability of ADCs and the contribution of the bispecific component. Challenging to see how this combo will fit into the TCE in 1L era

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@jitcancer @PathologyPat I still don’t understand why targeting TAMs isn’t considered a priority in oncology.

New #JITC article: "TAMing the tumor: targeting immune inhibitory receptors on tumor-associated macrophages in pediatric brain tumors – an emerging immunotherapy strategy" doi.org/10.1136/jitc-2…

🧬 Not all “pro-inflammatory” macrophages are anti-tumor. In ovarian cancer, a metastasis-associated inflammatory macrophage population may actively reprogram the peritoneal barrier to facilitate tumor invasion. A new Cell Death & Disease study identifies a striking communication circuit: IL-1α⁺ metastatic TAM → mesothelial cell → autocrine TGFβ → mesothelial-to-mesenchymal transition (MMT) → ovarian cancer invasion The work challenges the simplified idea that: M1 macrophage = anti-tumor M2 macrophage = pro-tumor. Instead, macrophage function appears strongly dependent on anatomical and cellular context. 🔬 Ascites and metastatic omentum contain very different macrophages The investigators performed scRNA-seq on matched tumor-associated macrophages from: ascites (ascTAMs) versus omental metastases (omTAMs) from high-grade ovarian cancer patients. Among 10,506 cells, they identified 11 TAM clusters with striking compartment-specific organization. Ascitic macrophages predominantly showed: M1low / M2high features. But metastatic omental TAMs displayed a much more inflammatory: M1⁺ / M2⁺ mixed phenotype. The UMAPs and M1/M2 maps in Figure 1, page 3 make this spatial polarization particularly clear. This matters because the metastatic macrophages were enriched for an entirely different functional program. 🔥 Omental TAMs carry a mesothelial-reprogramming signature Ovarian cancer commonly spreads through the peritoneal cavity. Before tumor cells can invade the omentum, however, they must overcome the protective mesothelial monolayer. One mechanism is: Mesothelial-to-mesenchymal transition (MMT) where mesothelial cells lose epithelial/barrier properties and acquire fibroblast-like, contractile and pro-invasive characteristics. The authors found that omTAMs were enriched for MMT-associated mediators including: MMP2 MMP9 WNT5A TNF IL1A TGFB2 PDGFA/B CCL5. Importantly, this MMT-driver program was concentrated in the M1⁺/M2⁺ metastatic macrophage population, rather than conventional M2-like ascitic TAMs. So the unexpected model becomes: pro-inflammatory macrophage → pro-metastatic stromal remodeling. 🧫 And the effect was functional—not merely transcriptomic. Conditioned medium from either experimentally generated M1 macrophages or patient-derived omTAMs transformed primary mesothelial cells. Mesothelial cells changed from their normal cobblestone morphology toward an elongated fibroblast-like phenotype. They showed: CDH1 ↓ KRT19 ↓ and: FN1 ↑ SNAI1 ↑. They also became more contractile. Most importantly: reprogrammed mesothelial cells allowed greater ovarian cancer-cell invasion through the mesothelial layer. Figure 4 on page 6 nicely connects the entire phenotype: omTAM secretome → morphology change → epithelial-marker loss → mesenchymal-marker gain → collagen contraction → tumor invasion. This converts macrophage heterogeneity into a biologically meaningful metastatic mechanism. 🧬 Which macrophage factor drives MMT? Proteomic profiling identified 123 proteins increased in inflammatory macrophage-conditioned medium, including 27 secreted EMT-associated factors. Several inflammatory cytokines could partially alter mesothelial morphology: IL-1α IL-1β TNFα IFNγ. But the decisive experiment was neutralization. Only IL-1α blockade significantly suppressed macrophage-induced MMT. Neutralizing IL-1α reduced: mesenchymal morphology FN1 expression collagen contraction. Blocking IL-1β or TNFα did not reproduce this effect. Figure 6 on page 8 is particularly compelling: IL-1α neutralization shifts mesothelial cells back toward their epithelial phenotype and reduces contractility. Patient-derived data reinforced the result. IL-1α secretion was significantly higher in omTAMs than ascTAMs, while single-cell data localized IL1A predominantly to metastatic omTAM clusters. And histology showed: CD68⁺ / IL-1α⁺ macrophages adjacent to peritoneal micrometastases. The clinical images in Figure 7, page 10 provide an important bridge from the in-vitro mechanism back to human disease. 🔄 But IL-1α does not act alone. This is where the mechanism becomes especially interesting. Inflammatory macrophages activated two parallel signaling systems in mesothelial cells: IL-1α → ERK + p38 MAPK and TGFβ → SMAD Pharmacological inhibition of MEK, p38 or TGFβ signaling attenuated MMT, with the strongest effect produced by TGFβ blockade. But where was all the TGFβ coming from? Surprisingly: the mesothelial cell itself. Mesothelial cells were a major TGFβ1 source, and exposure to inflammatory macrophages increased mesothelial: TGFβ1 secretion ↑ and TGFBR1 expression ↑. Thus macrophage IL-1α effectively converts the mesothelial cell into its own MMT amplifier: IL-1α ↓ IL1R1 → ERK/p38 ↓ TGFβ production ↑ + TGFBR1 ↑ ↓ autocrine TGFβ/SMAD ↓ self-reinforcing MMT This is beautifully summarized in Figure 8E on page 11. 🔥 The synergy experiment is probably the strongest mechanistic result. Neither recombinant IL-1α nor TGFβ alone completely reproduced macrophage-induced MMT. But: IL-1α + TGFβ → full MMT phenotype. Conversely: IL-1α blockade + TGFβ inhibition → essentially complete suppression of macrophage-induced MMT. Only combined IL-1α + TGFβ stimulation reproduced the strong collagen-contractile phenotype produced by inflammatory macrophages. So the proposed metastatic circuit becomes: Omental metastatic niche ↓ M1⁺/M2⁺ inflammatory TAM ↓ IL-1α ↓ mesothelial ERK/p38 activation ↓ TGFβ ↑ + TGFBR1 ↑ ↓ autocrine TGFβ/SMAD amplification ↓ MMT ↓ mesothelial barrier disruption ↓ transmesothelial ovarian cancer invasion That is a compelling example of a tumor exploiting immune–stromal communication, rather than tumor-cell-autonomous signaling, to establish metastasis. 💊 Could IL-1α therefore be therapeutically targeted? Potentially—but the timing may be crucial. IL-1α-neutralizing approaches such as bermekimab, and IL-1 receptor blockade such as anakinra, provide pharmacological precedent. However, previous IL-1α blockade in advanced metastatic cancer has not produced convincing tumor-directed efficacy; a phase III colorectal cancer study was terminated for futility. The authors therefore raise a more interesting therapeutic hypothesis: IL-1α blockade may be better suited to preventing metastatic niche formation than shrinking established tumors. For ovarian cancer, that could mean exploring it in an: adjuvant / minimal residual disease / early dissemination setting rather than late-stage refractory disease. The therapeutic objective would change from: kill established tumor to: prevent the peritoneum from becoming permissive to metastatic implantation. ⚠️ Important caveats The mechanistic work relies heavily on in-vitro conditioned-medium and coculture systems. The authors acknowledge that these cannot reproduce the full spatial and cellular complexity of the ovarian TME. The primary scRNA-seq discovery dataset also involved only three patients, although several findings were validated with additional patient-derived macrophages, proteomics, external single-cell datasets and clinical histology. Most importantly, there is not yet an in-vivo demonstration that: IL-1α inhibition → MMT ↓ → ovarian metastasis ↓. That is the crucial next experiment. Still, the conceptual message is strong: Inflammation is not synonymous with antitumor immunity. A macrophage can simultaneously exhibit an inflammatory/M1-like program and promote metastasis by remodeling surrounding stromal cells. The classical: M1 = good M2 = bad framework therefore misses the real biology. A better model is: TAM phenotype × anatomical niche × secretome × target cell = biological function. And in ovarian cancer, an IL-1α⁺ inflammatory macrophage → mesothelial TGFβ feedback circuit may help transform a protective peritoneal barrier into a metastatic niche. 📄 Heidemann S, Finkernagel F, Steitz AM, et al. A pro-inflammatory metastasis-associated macrophage subset induces tumor-promoting mesothelial cell conversion in ovarian cancer via IL-1α secretion. Cell Death & Disease. 2026;17:794. DOI: 10.1038/s41419-026-09280-1 #OvarianCancer #CancerResearch #TumorMicroenvironment #Macrophages #TAM #IL1alpha #TGFbeta #Metastasis #MMT #CancerImmunology #SingleCell #Proteomics #CellDeathDisease

It is possible hematopoietic aging could reflect replacement of a niche-maintaining macrophage population rather than deterioration of HSCs alone. When embryonic macrophages were absent, HSCs cycled more, apparently compensating for the reduced numbers. nature.com/articles/s4146…

Pain producing neurons around #cancer generate immune suppressive molecules... The neuroimmunology of cancer is crazy...and its an area that is highly overlooked.... nature.com/articles/s4158…

Macrophages eating living cells...NATURE paper ! nature.com/articles/s4158…

FDA clears trial of dual-targeted CAR T-cell therapy for cancer news-medical.net/news/20260911/…

🧬 IGF signaling is far more than a “growth pathway.” It may be one of biology’s central switches connecting nutrition, metabolism, tissue repair, aging—and cancer. A comprehensive 2026 review in Signal Transduction and Targeted Therapy maps the IGF/IGFR signaling network from basic physiology to disease and therapeutic development. At its core, the system contains: IGF1 + IGF2 → IGF1R / InsR → IRS & SHC → PI3K–AKT–mTOR + RAS–RAF–MEK–ERK with IGFBP1–6, proteases such as PAPPA/PAPPA2, and IGF2R controlling ligand availability and turnover. But the key message is that this is not a linear signaling pathway. 🔥 IGF is a signaling hub. The network communicates extensively with: Insulin EGFR HER2 PDGFR VEGF JAK–STAT TGF-β/BMP Wnt/β-catenin Notch ROR1 and these interactions can fundamentally change the biological output of IGF signaling. The network diagram on page 7 captures this complexity particularly well: IGF1R/InsR sit inside an interconnected signaling architecture converging on AKT, ERK, STAT and transcriptional programs governing metabolism, proliferation, differentiation and survival. This helps explain an apparent biological paradox. 🧓 Lower IGF signaling can promote longevity… Reduced insulin/IGF signaling is among the most conserved longevity mechanisms across species. In C. elegans, disruption of the IGF1R-related DAF-2 pathway can approximately double lifespan. Reduced IGF signaling also extends lifespan in flies, while mammalian effects show important sex dependence: reduced IGF1/IGF1R activity preferentially improves lifespan and healthspan in female mice. Remarkably, late-life IGF1R antibody treatment also extended lifespan and healthspan selectively in female mice. PAPP-A provides another fascinating example. Because PAPP-A cleaves IGFBPs and thereby increases local IGF bioavailability: PAPP-A loss → local IGF signaling ↓ → lifespan ↑ in mouse models. But simultaneously… 💪 IGF signaling is essential for maintaining tissues. Exercise can increase circulating and locally produced muscle IGF1, supporting: muscle repair hypertrophy anabolic adaptation. Even the vascular component matters for muscle aging: endothelial-specific IGF1R deficiency disrupts microvascular homeostasis, reduces skeletal-muscle perfusion and impairs exercise endurance—potentially relevant to age-related sarcopenia. Similarly, IGF1/IGF1R contributes to: bone mechanotransduction osteoblast function fracture repair cardiac function vascular homeostasis neural survival. So the aging biology is not simply: IGF ↓ = good. It is closer to: Too much chronic growth signaling may accelerate aging, while insufficient tissue-specific IGF signaling compromises maintenance and regeneration. 🧠 Alzheimer’s disease illustrates this paradox beautifully. IGF1 can reduce Aβ production through BACE1 downregulation and inhibit tau hyperphosphorylation through GSK3β suppression. IGF2 may also preserve cholinergic function and appears reduced in AD brains. Yet experimental reduction of neuronal IGF1R signaling can also enhance Aβ clearance and attenuate AD pathology. Again: ligand ≠ receptor abundance ≠ pathway activity ≠ tissue-specific biological outcome. Context matters. 🧬 Cancer exploits the same system. IGF signaling can support: proliferation survival stemness angiogenesis invasion metastasis therapy resistance. In NSCLC, for example, IGF1R overexpression has been associated with tumor progression, recurrence and poorer survival. IGF1R can also induce the immunosuppressive protein B7-H4 through MEK/ERK, while IGF2–IGF1R signaling contributes to acquired EGFR-TKI resistance. An especially interesting resistance circuit is: IL-6 → IGF1/2 ↑ → IGF1R → STAT3 → IGF1R transcription ↑ creating an autocrine IL-6/IGF1R/STAT3 loop capable of supporting EMT and EGFR-TKI resistance. This is highly relevant to precision oncology because IGF1R can function as a bypass pathway rather than the original oncogenic driver. For EGFR-mutant lung cancer: EGFR inhibition ↓ adaptive IGF1R signaling ↓ survival and preclinical transient IGF1R inhibition plus osimertinib has shown strong activity in selected contexts. 💊 So why did IGF1R cancer drugs largely disappoint? This may be the most instructive part of the review. Multiple anti-IGF1R antibodies reached clinical development: figitumumab cixutumumab ganitumab dalotuzumab R1507 along with IGF1R/InsR TKIs and ligand-neutralizing strategies. Yet most oncology programs failed to produce durable clinical success. The biology explains why. 1️⃣ InsR-A provides an escape route Cancer cells can redirect signaling through: IGF2 → InsR-A when IGF1R is blocked. IGF1R/InsR hybrid receptors further complicate inhibition. 2️⃣ Other RTKs compensate EGFR, HER2 and integrins create redundant signaling networks. 3️⃣ Downstream mutations bypass the receptor PI3K mutation / PTEN loss → AKT signaling persists even when IGF1R is inhibited. 4️⃣ Dual IGF1R/InsR inhibition creates metabolic toxicity IGF1R and InsR kinase domains are highly homologous. Blocking both can produce: hyperglycemia + insulin resistance → dose reduction → insufficient antitumor exposure. 5️⃣ Perhaps most importantly: patients were poorly selected. Many trials treated molecularly unselected populations, despite IGF dependence being profoundly context-specific. The authors identify inadequate biomarker stratification as a major contributor to clinical failure. This may be the central translational lesson: The failure of first-generation IGF1R drugs does not necessarily mean the IGF axis is a bad target. It may mean that “IGF1R-positive cancer” was the wrong biomarker. 🎯 The future may therefore be precision modulation—not global blockade. The organ-level schematic on page 15 makes the challenge obvious: the same IGF network participates in cancer, metabolism, cardiovascular biology, skeletal muscle, bone, immunity and neurobiology. Systemically turning IGF signaling simply ON or OFF is therefore biologically crude. A better framework may be: Which ligand? Which receptor/isoform? Which IGFBP? Which cell type? Which downstream state? Which disease stage? Which compensatory pathway? Then intervene selectively. This is particularly important for aging and sarcopenia. The therapeutic goal may not be to globally raise IGF1—potentially enhancing unwanted proliferative signaling—or globally suppress it and compromise muscle/bone repair. Instead: Preserve regenerative IGF signaling in muscle, vasculature and bone while suppressing maladaptive IGF signaling in tumors or other pathological compartments. That is a fundamentally different therapeutic concept. And it fits the review’s broader conclusion: IGF is not simply a growth factor pathway. It is a context-dependent systems-level regulator of the trade-off between growth, metabolism, repair, disease and longevity. The next generation of IGF therapeutics will probably succeed only when we stop asking: “Should IGF signaling be activated or inhibited?” and start asking: “Where, when, and in which molecular context should we modulate it?” 📄 Dilawar M, Malik A, Liao J, et al. Insulin-like growth factor receptor signaling in physiology and disease. Signal Transduction and Targeted Therapy. 2026;11:375. DOI: 10.1038/s41392-026-02843-w #IGF1 #IGF1R #IGF2 #IGFBP #Aging #Longevity #Sarcopenia #CancerMetabolism #CancerResearch #NSCLC #InsulinResistance #Geroscience #PrecisionMedicine #SignalTransduction

1/ I would LOVE to write a other thread about $BNTX PD-L1/VEGF bispecific (Pumitamig) + elfe-d B7H3 ADC combo in advanced SCLC, but I am taking way too much time of my vacation for these posts. I'll restrict it to source material: apexonco.com/node/2339/ onclive.com/view/pumitamig…

頭蓋骨骨髄は「脳のすぐ隣の免疫器官」である―Nature論文と慢性疼痛研究が示す新しい神経免疫の世界 - ２つの論文を合わせると，#頭蓋骨骨髄 が自然免疫と獲得免疫の双方に関わる，脳に最も近い免疫監視拠点である可能性が浮かび上がります．慢性疼痛だけでなく，認知症，脳卒中，脳腫瘍，自己免疫性脳炎，神経変性疾患などでも，頭蓋骨骨髄がどのように関与するのか注目されます．pkcdelta.hatenablog.com/entry/2026/09/…

🆙#WCLC26 #LCSM Oral Session 🔥Phase 1 Study of LB2102, a dnTGFBR2-armored DLL3-targeted Autologous CAR-T Cell Therapy, in Subjects With Relapsed or Refractory SCLC or LCNEC 🎙️Dr. Alberto Chiappori 🔢OA05.02 🎯Overall ORR SCLC 33.3%, LCNEC 0% ☑️NCT05680922 🔗 cattendee.abstractsonline.com/meeting/21487/… @OncoAlert @Larvol @IASLC

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Crazy Nature paper...killing tumor associated bacteria by liposome tumor-targeted antibiotics increases tumor immunogenicity and killing by immune system. nature.com/articles/s4158…

What if T cells could eliminate tumors without recognizing tumor-specific antigens at all? Immunotherapy has traditionally relied on tumor-specific T cells—or engineering T cells to recognize a defined tumor antigen. This study challenges that paradigm. Researchers show that activating unexhausted, bystander T cells within tumors can drive tumor elimination even in the absence of tumor-specific TCRαβ⁺ T cells. Rather than killing through conventional antigen recognition, robust T-cell activation triggered a broader immune cascade: recruitment of additional immune cells, activation of innate leukocytes, and production of a tumoricidal combination of IFN-γ, TNF, and nitric oxide, ultimately inducing caspase-dependent tumor cell death and panoptotic pathways. Even more intriguing, the gene-expression signatures associated with this response in mice were predictive of survival in patients with melanoma. The bigger story is a potential shift in how we think about cancer immunotherapy: Perhaps the T cell does not always need to recognize the tumor—it may simply need to be productively activated within the tumor. 🎯 That opens a fundamentally different therapeutic strategy: instead of generating or rescuing cancer-specific T-cell responses, could we harness the tumor microenvironment itself to turn bystander immunity into a coordinated antitumor weapon? A provocative concept—and one that could reshape how we think about “tumor specificity” in immunotherapy. nature.com/articles/s4159…

🧬 What if mitochondrial ATP does more than power T cells—what if it directly helps determine their identity by controlling chromatin accessibility? A fascinating new Cell study provides a mechanistic bridge between immunometabolism and epigenetics, showing that mitochondrial ATP production can support the chromatin remodeling required for CD8⁺ T-cell effector differentiation. The key molecule is D-α-hydroxybutyrate (DAHB). Rather than functioning primarily as a fuel, DAHB acts as a metabolic signal that reprograms activated CD8⁺ T cells: DAHB → OXPHOS ↑ → fatty-acid oxidation ↑ → phosphocreatine ↑ → local ATP buffering → BAF-dependent chromatin remodeling → effector genes ↑ → stronger antitumor immunity. That is a remarkable metabolism-to-chromatin circuit. 🔥 DAHB pushes CD8⁺ T cells toward a cytotoxic phenotype DAHB strongly increased: Perforin IFN-γ TNF-family members GZMB CCL3/CCL4 and DAHB-pretreated OT-I cells showed approximately 3-fold greater tumor-cell cytotoxicity. But the metabolic mechanism was unexpected. DAHB increased ATP-coupled mitochondrial respiration while suppressing glycolysis. Estimated ATP production shifted substantially: OXPHOS-derived ATP ↑ ~82% glycolytic ATP ↓ ~23%. Stable-isotope tracing showed that DAHB itself was not meaningfully oxidized through the TCA cycle. Instead, it doubled fatty-acid oxidation and redirected glucose away from lactate production toward biosynthetic pathways, including the pentose-phosphate and serine/glycine pathways. So: DAHB is not primarily the fuel. It changes which fuels the T cell uses. ⚡ Then comes the central discovery: phosphocreatine Untargeted metabolomics identified phosphocreatine (PCr) as the most strongly induced metabolite after DAHB treatment. This is intriguing because the creatine–phosphocreatine system is usually associated with tissues such as skeletal muscle, heart and brain, where it rapidly transports and buffers high-energy phosphate. Here, activated T cells appear to exploit the same system. DAHB increased: OXPHOS → mitochondrial ATP → PCr ↑ → CKB ↑ and blocking phosphocreatine production with cyclocreatine or creatine-kinase inhibition: ⬇️ perforin ⬇️ IFN-γ ⬇️ tumor killing. Even more interestingly, CKB accumulated near the nuclear envelope, with DAHB producing >6-fold enrichment of CKB–Lamin B1 proximity signals. This suggests that PCr may function as an intracellular energy shuttle: mitochondria → PCr → nucleus → ATP delivering energetic capacity precisely where ATP-consuming nuclear processes occur. 🧬 And one of those processes is chromatin remodeling ATAC-seq showed that DAHB increased chromatin accessibility at key effector loci: Prf1 Ifng Tnf while inhibition of PCr synthesis largely reversed these changes. The investigators then targeted the ATP-dependent BAF/mSWI-SNF chromatin remodeling complex. Both BAF degradation and inhibition of its BRG1/BRM ATPase activity reduced DAHB-induced perforin and IFN-γ and eliminated the increased accessibility of effector loci. This creates an elegant mechanistic sequence: FAO ↓ mitochondrial OXPHOS ↓ ATP ↓ phosphocreatine ↓ nuclear ATP buffering ↓ BAF chromatin-remodeling activity ↓ open Prf1 / Ifng / Tnf loci ↓ CYTOTOXIC T-CELL DIFFERENTIATION The graphical abstract on page 1 captures this beautifully: mitochondrial ATP is converted into a PCr-based energetic shuttle that connects mitochondrial metabolism to nuclear BAF activity and ultimately cytotoxicity. 🎯 The antitumor consequences were substantial Ex vivo DAHB conditioning of antigen-specific OT-I cells improved control of EL4-OVA tumors after adoptive transfer. DAHB also enhanced anti-CTLA-4 therapy in immunocompetent MC38 colorectal cancer and B16 melanoma models, whereas this benefit disappeared in lymphocyte-deficient RAG2-KO mice—supporting an adaptive immune mechanism. Figure 6 on page 11 is especially compelling: DAHB improves tumor control across adoptive-transfer and checkpoint-blockade experiments. And the TIL phenotype is interesting. DAHB-treated tumors contained CD8⁺ T cells with: ⬆️ CD44 ⬆️ TCF1 ⬆️ antigen-specific gp100⁺ cells ⬇️ PD-1⁺CD39⁺ cells ⬆️ polyfunctional IFN-γ⁺TNF-α⁺ responses ⬆️ T-bet. Importantly, residual PD-1⁺CD39⁺ cells expressed more TCF1, suggesting enrichment toward a precursor-exhausted rather than terminally exhausted state. 👨‍⚕️ And the biology translated to human T cells Under chronic stimulation, DAHB-treated human CD8⁺ T cells maintained: IFN-γ ↑ TNF-α ↑ PCr ↑ ATP/ADP better preserved and cyclocreatine partially reversed these effects. Human CD8⁺ T cells engineered with the NY-ESO-1-specific 1G4 TCR also showed greater cytokine production and stronger killing of A375 melanoma cells after DAHB treatment. Most importantly, in an A375 xenograft model: DAHB alone → little effect on tumor growth but 1G4 T-cell ACT + DAHB → significantly improved tumor control. That distinction argues that DAHB is functioning primarily as a metabolic adjuvant for T cells, rather than simply acting directly on cancer cells. 💡 The conceptual implication is broader than DAHB We often describe mitochondrial metabolism as providing enough ATP for cells to “function.” This study suggests something more specific: Energy availability can regulate cell fate because chromatin remodeling itself has an energetic cost. ATP is therefore not merely downstream fuel for an already differentiated effector T cell. Mitochondrial energy production may participate directly in establishing the epigenetic accessibility required to become and remain an effector cell. That has potentially important implications for: CAR-T manufacturing TCR-engineered T cells tumor-infiltrating lymphocytes checkpoint blockade metabolic preconditioning of adoptive cell therapies. Instead of engineering only receptors and signaling domains, perhaps we should also engineer the bioenergetic infrastructure that maintains their chromatin state. There are important caveats. The molecular sensor through which DAHB activates mitochondrial ETC activity remains unknown. The concentrations used experimentally were high, whether microbiota-derived DAHB ever reaches comparable concentrations in vivo is unclear, and the safety/tolerability of therapeutic systemic DAHB in humans remains untested. Still, the mechanistic concept is striking: MITOCHONDRIA → ATP → PHOSPHOCREATINE → BAF → CHROMATIN ACCESSIBILITY → T-CELL FATE → ANTITUMOR IMMUNITY Metabolism and epigenetics are not separate layers of T-cell biology. They may be connected by something as fundamental as where ATP is produced—and where that energy is delivered. 📄 Ng C, Fung TS, Li D, et al. Mitochondrial ATP promotes T cell differentiation through chromatin accessibility. Cell. 2026;189. DOI: 10.1016/j.cell.2026.08.023 #CancerImmunology #Immunometabolism #TCells #Mitochondria #OXPHOS #Phosphocreatine #Chromatin #Epigenetics #BAF #TCellExhaustion #Immunotherapy #CART #CellTherapy #CancerMetabolism