Leiy

enthusiast

[谷口研究室（北海道大学医学部 統合病理学教室） @iPatho1]

50種類のがん細胞株に約1,100の薬剤・用量条件を加えた1億細胞のシングルセルトランスクリプトームを収集し、薬剤作用と細胞応答を結び付ける大規模アトラスTahoe-100Mを構築したという論文がCell誌に発表されました。
https://t.co/vWdpF8hbWp

[Biomedical Picture of the Day BPoD @BPoD_s]

Two-way mitochondrial transfer between GBM tumour cells & astrocytes via nanotubes – a tumour adaptation that could be targeted

📹 Ines Saenz-de-Santa-Maria et al, Institut Pasteur, Université Paris Cité in @NatureComms
➡️ https://t.co/sK8UEYHQBA

[硅基人老王 @AI_oldwang]

如果我明天被裁员，必须立即补充收入，我会这样做：

1. 去Instagram开新账号。用备用邮箱。没人需要知道。

[Motoshi Hayano @HayanoMotoshi]

老化細胞はMICAなどのリガンドで免疫に認識される一方、PD-L1やGD3で監視から逃れる

老化細胞は本来、NK細胞やT細胞をはじめとする免疫細胞によって除去される運命にあるが、加齢とともにこの免疫監視機構が弱まり、老化細胞が組織中に蓄積してしまうことが知られている。

なぜ加齢に伴って免疫監視機能が低下するのか、また免疫細胞自体の老化がどのように監視機構全体に影響を及ぼすのかという相互作用については、理解が十分に進んでいなかった。

本レビューは、NK細胞、マクロファージ、好中球、樹状細胞、T細胞、B細胞のそれぞれが老化細胞をどのように認識・除去するか、そして老化細胞側が免疫チェックポイント分子などを駆使していかに免疫監視から逃れるかを整理している。免疫細胞自身の老化がさらに監視機能を弱めるという悪循環にも言及している。

分子レベルでは、老化細胞はMICA、ULBP2、MHCクラスI/IIといった免疫原性リガンドを提示することでNK細胞やT細胞に認識される一方、HLA-E、PD-L1、PD-L2、FasL、ガングリオシドGD3といった免疫チェックポイント様分子の発現やJAK-STAT・TGF-β-SMAD経路の活性化を通じて免疫監視から逃れるという、認識と回避の二面的な分子基盤が整理されている。

老化細胞除去薬（セノリティクス）に加えて、免疫系そのものを活用した新しいタイプの治療戦略という方向性を後押しする内容である。
https://t.co/8OC6Pka2gz

[谷口研究室（北海道大学医学部 統合病理学教室） @iPatho1]

27生物種・75組織、5億200万細胞超のsingle-cell RNA-seqデータをAIエージェントが自動収集・注釈・再解析し、継続更新する大規模データベースscBaseCountを構築したという論文がCell誌に発表されました。
https://t.co/QGL9T3Ej7Z

[nature @Nature]

Nature research paper: Mitochondrial fission factor senses and governs ferroptosis

https://t.co/WsvgjYyRI1

[Martin Pacesa @MartinPacesa]

This is so amazing, runs in seconds on a M5 Mac, my go to now

[오창명 @changmyung1981]

🧬 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

[Ming "Tommy" Tang @tangming2005]

Benchmarking biomedical foundation models https://t.co/8qXk1Pqv7h

[谷口研究室（北海道大学医学部 統合病理学教室） @iPatho1]

細胞周期・ゲノム維持関連遺伝子由来のイントロン保持RNAが核スペックル周辺に長期間蓄積し、有糸分裂時に同期してスプライシングされることで、遺伝子発現の時間的制御に寄与することを示した論文がNat Cell Biol誌に発表されました。
https://t.co/ScmoszkArp

[nature @Nature]

Nature research paper: Proximity-guided graph learning reveals tumour-associated proximity antigens

https://t.co/QjHRC87QoN

[LukeGilbert @LukeGilbertSF]

Cells mitigate damage to DNA in surprising ways. Using a series of CRISPRi chemogenomics screens, we identified a PRDX1-dependent iron–damage axis in the DNA damage response.
Congratulations to Tom, Abe, Shaheen, Josep and all co-authors!

https://t.co/TrtzP2T9Bw

[nature @Nature]

Nature research paper: Membranolytic peptide programs immunogenic cell death for cancer therapy

https://t.co/F0SKoZqwtR

[nature @Nature]

Nature research paper: Replication-stress-induced chromatin loops protect fork stability

https://t.co/Z8VxT2RYnS

[Cell @CellCellPress]

Now online! LEF1 and niche factors determine T cell stemness across chronic diseases https://t.co/ZPDtI2Tl8q

[Will Hua @itswillhua]

OpenDDE is not a simple reproduction of IsoDDE. We just want to build an open-source ecosystem towards REAL Drug Discovery Engine. The core is co-folding, but what's next? The next-preview release is about design.

[Bryan Johnson @bryan_johnson]

If you get cancer, your risk of Alzheimer's drops by about a third. If you get Alzheimer's, your risk of cancer drops by about half.

The body playing tug of war with itself.

Two diseases pulling against each other, using the same cellular mechanism in opposite directions.

[Cell Stem Cell @CellStemCell]

ZNF512B safeguards genome integrity at regulatory regions to repress the SASP and inflammation https://t.co/2iMBsBkui0

[Marinka Zitnik @marinkazitnik]

New @NatureMedicine paper: A pan-cancer foundation model predicts immunotherapy response and highlights the biology behind it

https://t.co/p27ERHIDew

@harvardmed news: https://t.co/A3OjmNGXJM

Roughly a quarter of patients with advanced cancer respond durably to immune checkpoint inhibitors. The rest endure toxicity and cost with little benefit, and existing tools, TMB, PD-L1 staining, remain unreliable across cancer types and drugs

COMPASS is a pan-cancer foundation model that predicts immunotherapy response from tumor transcriptomes and reveals the reasoning behind each prediction

@HarvardDBMI @harvardMed @Roche @Harvard @BroadInstitute @KempnerInstitute

[Uri Alon @UriAlonWeizmann]

Why do animals age in such similar ways, yet live for wildly different spans - from days to a century?
Our new paper in @NatureAging fits a damage accumulation model across 9 species and finds the knob that best predicts lifespan
https://t.co/i5xIkQ6jDT