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Reprogramming regulatory T cell plasticity for cancer immunotherapy
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DOI：10.1016/j.bbcan.2026.189605.png)
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Abstract
En 中文
Regulatory T cells (Tregs) maintain immune homeostasis by suppressing excessive immune responses. In the context of cancer, Tregs are abundantly recruited to inhibit immunity against tumoral cells, facilitate immune evasion, and promote tumor progression. While Treg depletion strategies have repeatedly failed in the clinic due to severe autoimmune side effects, lack of specificity, and rapid compensatory recruitment, a critical unmet need remains for safer and more effective approaches. Emerging evidence highlights the remarkable plasticity of Tregs, allowing them to adopt an inflammatory phenotype in response to tumor-associated cytokines. Thus, leveraging this plasticity, rather than attempting broad depletion, may represent a superior anticancer strategy. This plasticity is marked by the expression of transcription factors like T-bet (Th1-like) and RORγt (Th17-like), the production of pro-inflammatory cytokines such as IFN-γ and IL-17, and even the acquisition of differential energetic preferences pertaining to glucose or glutamine. These changes can weaken Treg suppressive functions or paradoxically enhance inflammation in the tumor microenvironment, thereby creating a complex interplay between immune suppression and anti-tumor effector activity. Understanding the molecular cues driving Treg plasticity is therefore critical for designing novel therapies that shift Tregs toward an effector-like state, ultimately enhancing anti-tumor immunity and improving the efficacy of current immunotherapies. This review offers a fresh perspective on how Treg plasticity can be therapeutically harnessed to overcome the persistent limitations of conventional Treg-targeted approaches.
Keywords:
Treg cells
Treg plasticity
Antitumor immunity
Immune phenotypes
Immune infiltration
Tregs
regulatory T cells
TME
tumor microenvironment
CD25
IL-2 receptor α-chain
TGF-β
transforming growth factor-beta
IL
interleukin
nTregs
natural Tregs/thymic Tregs
iTregs
induced Tregs/peripheral Tregs
trTregs
tissue-resident Tregs
eTregs
effector regulatory T cells
mTregs
memory Tregs
TCR
T cell receptor
Foxp3
Forkhead box protein p3
IFN-γ
interferon-gamma
CTL
cytotoxic T lymphocyte
T-bet
T-box expressed in T cells
STAT
signal transducer and activator of transcription
GITR
glucocorticoid-induced TNFR-related protein
ChIP-seq
chromatin immunoprecipitation sequencing
T1D
type 1 diabetes/autoimmune diabetes
HIF-1α
hypoxia-inducing factor 1-alpha
FA
fatty acid
mTOR
mammalian target of rapamycin
OXPHOS
oxidative phosphorylation
FAO
fatty acid oxidation
GLUT
glucose transporter
HK
hexokinase
LDH
lactate dehydrogenase
mTORC1
mTOR complex 1
GLS
glutaminase
α-KG
alpha-ketoglutarate
GDH
glutamate dehydrogenase
TCA
tricarboxylic acid
IDO
indoleamine 2,3-dioxygenase
S6K1
ribosomal protein S6 kinase
4E-BP1
eukaryotic translation initiation factor 4E-binding protein 1
CPT
carnitine palmitoyltransferase
OCR
oxygen consumption rate
MDSCs
myeloid-derived suppressor cells
ICIs
immune checkpoint inhibitors
CRC
colorectal cancer
s.c.
subcutaneous
ECAR
extracellular acidification rate
HBP
hexosamine biosynthetic pathway
orCC
oropharyngeal squamous cell carcinoma
HPV
human papillomavirus
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