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Protein S‑palmitoylation in T cell‑mediated antitumor immunity: Context‑dependent mechanisms and therapeutic opportunities (Review)

  • Authors:
    • Shiting Wang
    • Rui Xu
    • Sikan Jin
    • Ting Yu
    • Ming Qin
    • Lin Xu
    • Xianyao Wang
  • View Affiliations / Copyright

    Affiliations: Department of Immunology, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China, Key Laboratory of Cancer Prevention and Treatment of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
    Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 367
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    Published online on: November 4, 2026
       https://doi.org/10.3892/ijmm.2026.6038
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Abstract

S‑palmitoylation is a critical post‑translational regulator of protein function; however, its role in T cell‑mediated antitumor immunity remains unclear. The present review summarizes emerging evidence that redefines T cell biology and its implications for antitumor immunity. The regulatory functions of S‑palmitoylation in T cell receptor signaling, activation, proliferation, differentiation, exhaustion and apoptosis are first outlined, highlighting the distinct roles of the zinc finger Asp‑His‑His‑Cystype family of palmitoyl acyltransferases and depalmitoylating enzymes in modulating the membrane localization, stability and signal transduction of key T cell signaling regulators. How S‑palmitoylation of immune checkpoints, such as programmed death‑ligand 1, and the components of antigen presentation shape the tumor immune microenvironment were further examined. Additionally, the recent advances in therapeutic strategies targeting S‑palmitoylation, including small‑molecule inhibitors, peptide‑based interventions and nanoparticle delivery systems, were highlighted, and their potential to enhance T cell antitumor immunity, particularly in combination with immune checkpoint blockade, was discussed. Finally, the current challenges, including the suboptimal selectivity of pharmacological agents, technical limitations of existing delivery systems and the intrinsic heterogeneity and immunosuppressive nature of the tumor microenvironment were discussed, and future directions for advancing S‑palmitoylation‑targeted immunotherapies were proposed. Collectively, the present review highlights S‑palmitoylation as a promising regulatory axis for antitumor immunity and provides a foundation for the future development of targeted immunotherapies.
View Figures

Figure 1

S-palmitoylation orchestrates T cell
signaling activation, proliferation, differentiation, exhaustion
and apoptosis. (A) T cell-intrinsic mechanisms. S-palmitoylation
promotes the membrane localization and lipid raft partitioning of
key T cell receptor-associated signaling molecules, including Lck,
Fyn, LAT and CD4/CD8, facilitating ZAP-70 recruitment and LAT
signalosome assembly. These membrane-proximal events activate
downstream pathways, including PLCγ1, Ras-MAPK and
calcium-dependent signaling cascades, which ultimately drive T cell
activation, proliferation and effector differentiation.
Palmitoylated Ras isoforms (N-Ras and H-Ras) are depicted. (B)
Innate immune pathways. S-palmitoylation dynamically regulates the
localization, trafficking, stability and signaling activity of
innate immune regulatory proteins. TLR4/IL-1R signaling through
MyD88-IRAK1/4-TRAF6 converges on the classical (TAK1/NEMO/IKKβ)
NF-κB activation pathway, whereas TNFR1 signaling through
TRADD/TRAF2 converges on the non-canonical (NIK/IKKα) NF-κB
activation pathway. (C) Adaptive immune responses. S-palmitoylation
of immune checkpoint molecules, including PD-1 and TIM-3, enhances
receptor stability by promoting receptor recycling (such as Rab11)
or preventing lysosomal degradation (such as HRD1), thereby
sustaining inhibitory signaling and contributing to T cell
exhaustion and tumor immune evasion. S-palmitoylation also
regulates TNFR1 and CKR/JAK2/STAT3 signaling (CKs include TGF-β,
IL-6 and IL-23; CKR denotes the corresponding receptors), as well
as Fas/FasL membrane organization, to modulate apoptotic signaling
and immune homeostasis. FoxP3 S-palmitoylation facilitates its
nuclear accumulation and maintains regulatory T cell suppressive
function. Figure created with BioRender.com. ZAP-70, ζ-chain-associated protein
kinase 70; LAT, linker for activation of T cells; PLCγ1,
phospholipase C γ1; NF-κB, nuclear factor κB; STAT3, signal
transducer and activator of transcription 3; FoxP3, forkhead box
P3; PD-1, programmed cell death protein 1; PD-L1, programmed
death-ligand 1; TIM-3, T cell immunoglobulin and mucin-domain
containing-3; TNFR1, tumor necrosis factor receptor 1; CKs,
cytokines; CKR, cytokine receptor; JAK2, Janus kinase 2; Fas, Fas
cell surface death receptor; FasL, Fas ligand; Pal,
S-palmitoylation; Depal, depalmitoylation.

Figure 2

Spatial regulation of protein
S-palmitoylation in the tumor immune microenvironment. Left panel:
schematic overview of the TME, illustrating the interaction between
cancer cells and CD8+ T cells. Right panel: magnified
view of S-palmitoylation-mediated regulation of key
immune-regulatory and metabolic proteins in tumor cells. B7-H4 is
palmitoylated in the Golgi apparatus, which protects it from
lysosomal degradation and sustains its immunosuppressive function.
IFNGR1 S-palmitoylation, in coordination with optineurin, prevents
AP3D1-mediated lysosomal sorting and degradation, preserving IFN-γ
signaling integrity. S-palmitoylation of PD-L1 prevents its
ubiquitination and subsequent ESCRT-mediated lysosomal degradation,
thereby sustaining PD-L1 surface expression and attenuating
CD8+ T cell-mediated antitumor immunity.
S-palmitoylation of B7H3 disrupts its interaction with the
autophagy receptor SQSTM1/p62, limiting autophagic degradation and
enhancing B7H3 stability, which further suppresses CD8+
T cell activity. In addition, S-palmitoylation of FASN disrupts its
interaction with the TRIM28-SNX8 E3 ubiquitin ligase complex,
thereby preventing ubiquitin-proteasome-mediated degradation and
promoting de novo fatty acid synthesis. Collectively, these
spatially regulated S-palmitoylation events promote tumor immune
evasion and metabolic adaptation. Figure created with BioRender.com. PD-L1, programmed death-ligand 1;
B7H3, B7 homolog 3; B7-H4, B7 homolog 4; IFNGR1, interferon γ
receptor 1; FASN, fatty acid synthase; ESCRT, endosomal sorting
complex required for transport; Ub, ubiquitin; Pal,
S-palmitoylation; TME, tumor microenvironment.

Figure 3

Therapeutic strategies targeting
S-palmitoylation to enhance antitumor responses. S-palmitoylation
is a promising target that can be combined with chemotherapy,
metabolic intervention and immune checkpoint blockade to improve
cancer treatment efficacy. (A) Chemosensitization and resistance
reversal. siRNA-mediated inhibition of ZDHHC12 increases cisplatin
sensitivity in ovarian cancer. Targeting ZDHHC2 with TTZ1 reduces
USP19 S-palmitoylation, thereby preventing ubiquitin-proteasome
degradation of ACSL4, promoting ferroptosis and reversing
enzalutamide resistance in prostate cancer. (B) Metabolic
intervention. The CPT1A/ZDHHC4/MAVS axis promotes MAVS
S-palmitoylation and type I interferon signaling. PF-670462
promotes ZDHHC8 degradation, thereby reducing GPX4
S-palmitoylation, leading to GPX4 degradation and enhanced
ferroptosis. (C) Immune checkpoint blockade. The E-peptide disrupts
ZDHHC24-mediated B7H3 S-palmitoylation, promoting B7H3 degradation
and improving anti-PD-1 responses. Inhibition of FASN reduces
palmitate synthesis, thereby decreasing PD-L1 S-palmitoylation and
restoring sensitivity to immune checkpoint blockade. Figure created
with BioRender.com. ICB, immune checkpoint
blockade; ZDHHC, zinc finger DHHC-type palmitoyltransferase; CPT1A,
carnitine palmitoyltransferase 1A; MAVS, mitochondrial antiviral
signaling protein; GPX4, glutathione peroxidase 4; FASN, fatty acid
synthase; PD-1, programmed cell death protein 1; PD-L1, programmed
death-ligand 1; B7H3, B7 homolog 3; ACSL4, acyl-CoA synthetase
long-chain family member 4.
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Copy and paste a formatted citation
Spandidos Publications style
Wang S, Xu R, Jin S, Yu T, Qin M, Xu L and Wang X: Protein S‑palmitoylation in T cell‑mediated antitumor immunity: Context‑dependent mechanisms and therapeutic opportunities (Review). Int J Mol Med 58: 367, 2026.
APA
Wang, S., Xu, R., Jin, S., Yu, T., Qin, M., Xu, L., & Wang, X. (2026). Protein S‑palmitoylation in T cell‑mediated antitumor immunity: Context‑dependent mechanisms and therapeutic opportunities (Review). International Journal of Molecular Medicine, 58, 367. https://doi.org/10.3892/ijmm.2026.6038
MLA
Wang, S., Xu, R., Jin, S., Yu, T., Qin, M., Xu, L., Wang, X."Protein S‑palmitoylation in T cell‑mediated antitumor immunity: Context‑dependent mechanisms and therapeutic opportunities (Review)". International Journal of Molecular Medicine 58.6 (2026): 367.
Chicago
Wang, S., Xu, R., Jin, S., Yu, T., Qin, M., Xu, L., Wang, X."Protein S‑palmitoylation in T cell‑mediated antitumor immunity: Context‑dependent mechanisms and therapeutic opportunities (Review)". International Journal of Molecular Medicine 58, no. 6 (2026): 367. https://doi.org/10.3892/ijmm.2026.6038
Copy and paste a formatted citation
x
Spandidos Publications style
Wang S, Xu R, Jin S, Yu T, Qin M, Xu L and Wang X: Protein S‑palmitoylation in T cell‑mediated antitumor immunity: Context‑dependent mechanisms and therapeutic opportunities (Review). Int J Mol Med 58: 367, 2026.
APA
Wang, S., Xu, R., Jin, S., Yu, T., Qin, M., Xu, L., & Wang, X. (2026). Protein S‑palmitoylation in T cell‑mediated antitumor immunity: Context‑dependent mechanisms and therapeutic opportunities (Review). International Journal of Molecular Medicine, 58, 367. https://doi.org/10.3892/ijmm.2026.6038
MLA
Wang, S., Xu, R., Jin, S., Yu, T., Qin, M., Xu, L., Wang, X."Protein S‑palmitoylation in T cell‑mediated antitumor immunity: Context‑dependent mechanisms and therapeutic opportunities (Review)". International Journal of Molecular Medicine 58.6 (2026): 367.
Chicago
Wang, S., Xu, R., Jin, S., Yu, T., Qin, M., Xu, L., Wang, X."Protein S‑palmitoylation in T cell‑mediated antitumor immunity: Context‑dependent mechanisms and therapeutic opportunities (Review)". International Journal of Molecular Medicine 58, no. 6 (2026): 367. https://doi.org/10.3892/ijmm.2026.6038
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