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Review Open Access

Targeting ICMT: A promising strategy in cancer treatment (Review)

  • Authors:
    • Jinghong Hu
    • Ying Xiao
    • Jingyi Tang
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    Affiliations: School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, P.R. China
    Copyright: © Hu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 152
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    Published online on: March 2, 2026
       https://doi.org/10.3892/ol.2026.15506
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Abstract

Protein prenylation is a prevalent post‑translational modification of proteins, pivotal in regulating their biological functions. It influences critical cellular processes such as signal transduction, cell cycle control and apoptosis. Isoprenylcysteine carboxymethyltransferase (ICMT) serves as the terminal enzyme in this pathway, catalyzing the methylation of proteins containing‑CAAX or ‑CXC motifs, thereby modulating their subcellular localization and biological activity. Accumulating evidence indicates that ICMT inhibition disrupts key malignant phenotypes, such as tumor cell proliferation, migration and invasion, and attenuates the functional dependency of RAS proteins on prenylation. Consequently, ICMT has emerged as an important regulator of cancer‑associated signaling and a potential therapeutic target. This review summarizes current knowledge on ICMT‑mediated protein modification, its regulatory mechanisms and its roles in cancer progression, with the aim of highlighting recent advances and discussing the therapeutic implications of targeting ICMT in oncology. 
View Figures

Figure 1

Three steps of CAAX protein
prenylation. After the RAS gene is transcribed and translated on
the ribosome, it is anchored to the endoplasmic reticulum membrane
for further modification. First, a 15-carbon (farnesyl) or
20-carbon (geranyl) isoprenoid lipid is covalently attached to a
cysteine residue by protein FTase or GGTase I. Subsequently, the
-AAX tripeptide is cleaved by RCE1, a protease that catalyzes
endoproteolytic hydrolysis. Finally, ICMT catalyzes the methylation
of the cysteine-terminal α-carboxylic acid, completing the
modification. FTase, farnesyltransferase; GGTase I,
geranlygeranyltransferase I; RCE1, Ras-converting enzyme 1; ICMT,
isoprenylcysteine carboxymethyltransferase.

Figure 2

Timeline of ICMT research. In 1978,
chemical analyses from a study on fungal mating factor
rhodotorucine A revealed a farnesyl-like isoprene linked to the Cys
residue of the peptide via a thioether bond (9); in 1988, human RAS proteins were found
to be indeed farnesylated and this modification was required for
oncogenic RAS-transformed cells (10,11);
in the 1990s, the three-step modification process of CAAX protein
was reported to be catalyzed by FTase or GGTase I, RCE1 and ICMT,
respectively (2,12–15);
in 2004, inactivation of ICMT was found to inhibit the
transformation of oncogenic K-Ras and B-Raf (16); in 2010, inhibition of ICMT was
indicated to induce autophagy-dependent apoptosis and impair tumor
growth (17); in 2015, ICMT was
reported to regulate mitochondrial respiration and cancer cell
metabolism (18); in 2021,
inhibition of ICMT was indicated to impair DNA damage repair
(19); in 2024, ICMT was found to
promote the formation of invasive pseudopods and metastasis of
cancer cells (20). FTase,
farnesyltransferase; GGTase I, geranlygeranyltransferase I; RCE1,
Ras-converting enzyme 1; ICMT, isoprenylcysteine
carboxymethyltransferase.

Figure 3

Expression pattern of ICMT in
different cancer types and breast cancer cell lines. (A) Expression
of ICMT in 30 cancer types. It is expressed significantly higher in
testicular and prostate cancers, but lowest in adrenal cancer. The
data were generated using the Human Protein Atlas (https://www.proteinatlas.org). (B) Expression of ICMT
in 30 cancer types. The data were generated using cBioPortal
(https://www.cbioportal.org). (C)
Expression of ICMT in different breast cancer cells. The expression
of ICMT was the highest in SK-BR-3 and MDA-MB-330 cells. The data
were generated using Human Protein Atlas (https://www.proteinatlas.org). (D) Pie chart
illustrating the proportion of ICMT expression in luminal A,
luminal B, HER2 positive, triple negative A and triple negative B.
Among them, triple negative A and B and luminal A accounted for
~20%. ICMT, isoprenylcysteine carboxymethyltransferase; TCGA, The
Cancer Genome Atlas.

Figure 4

Summary of critical inhibitors
targeting Ras according to its molecular mechanism. Ras serves as a
crucial signaling node that coordinates multiple cellular processes
through three major effector pathways. The RAS-MAPK pathway,
activated by receptor tyrosine kinases (RTKs), transduces signals
through the RAF-MEK-ERK cascade to regulate cell proliferation and
differentiation. Simultaneously, the PI3K-AKT pathway promotes cell
survival and growth by converting PIP2 to PIP3 through PI3K, which
subsequently activates AKT to inhibit apoptotic signals.
Additionally, the RALGDS pathway modulates cytoskeletal dynamics
and vesicular trafficking, thereby influencing cell migration and
secretory functions. RTKs, receptor tyrosine kinases; MAPK,
mitogen-activated protein kinase; RAF, rapidly accelerated
fibrosarcoma kinase; MEK, MAPK kinase; ERK, extracellular
signal-regulated kinase; PI3K, phosphatidylinositol 3-kinase; PIP2,
phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol
3,4,5-trisphosphate; RALGDS, ral guanine nucleotide dissociation
stimulator.
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Copy and paste a formatted citation
Spandidos Publications style
Hu J, Xiao Y and Tang J: Targeting ICMT: A promising strategy in cancer treatment (Review). Oncol Lett 31: 152, 2026.
APA
Hu, J., Xiao, Y., & Tang, J. (2026). Targeting ICMT: A promising strategy in cancer treatment (Review). Oncology Letters, 31, 152. https://doi.org/10.3892/ol.2026.15506
MLA
Hu, J., Xiao, Y., Tang, J."Targeting ICMT: A promising strategy in cancer treatment (Review)". Oncology Letters 31.5 (2026): 152.
Chicago
Hu, J., Xiao, Y., Tang, J."Targeting ICMT: A promising strategy in cancer treatment (Review)". Oncology Letters 31, no. 5 (2026): 152. https://doi.org/10.3892/ol.2026.15506
Copy and paste a formatted citation
x
Spandidos Publications style
Hu J, Xiao Y and Tang J: Targeting ICMT: A promising strategy in cancer treatment (Review). Oncol Lett 31: 152, 2026.
APA
Hu, J., Xiao, Y., & Tang, J. (2026). Targeting ICMT: A promising strategy in cancer treatment (Review). Oncology Letters, 31, 152. https://doi.org/10.3892/ol.2026.15506
MLA
Hu, J., Xiao, Y., Tang, J."Targeting ICMT: A promising strategy in cancer treatment (Review)". Oncology Letters 31.5 (2026): 152.
Chicago
Hu, J., Xiao, Y., Tang, J."Targeting ICMT: A promising strategy in cancer treatment (Review)". Oncology Letters 31, no. 5 (2026): 152. https://doi.org/10.3892/ol.2026.15506
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