Protein S-Palmitoylation in Cancer: A Novel Target in Immunotherapy & Treatment

Abstract

Protein S-palmitoylation, a reversible lipid posttranslational modification, is important for the regulation of protein localization, stability, and function. S-palmitoylation has been recently shown to be important in tumorigenesis, immune response modulation, and resistance to cancer therapy. Selective targeting of S-palmitoylation offers a new strategy for promoting antitumor immunity and overcoming therapeutic resistance. This review delves into the newest developments in recognizing protein S-palmitoylation in tumor immunity, how it relates to immune evasion, and the way new therapeutic approaches are utilizing this modification to engineer novel cancer therapies. Through addressing the critical enzymes responsible for palmitoylation and depalmitoylation, as well as present issues with targeting these processes, this review discusses the promise of harnessing S-palmitoylation as a therapeutic target for oncology.

Introduction

Cancer is still one of the major causes of death globally, requiring new therapies to enhance patient survival. Tumor cells have evolved elaborate means of immune evasion, resistance to traditional treatments, and maintenance of uncontrolled growth. Protein S-palmitoylation, a reversible and dynamic post-translational modification, is a critical controller of protein function in oncogenicity and immune regulation. Through the regulation of protein trafficking, stability, and interaction with lipid membranes, S-palmitoylation has direct effects on tumor growth, immune cell signaling, and response to therapy. Here, the contribution of S-palmitoylation to tumor immunity, its influence on cancer therapy, and prospects for targeting this modification in therapy are discussed.

Protein S-Palmitoylation: Mechanisms and Regulation

S-palmitoylation is the addition of a 16-carbon palmitate chain to cysteine residues on target proteins through a family of zinc finger DHHC (Asp-His-His-Cys) protein acyltransferases (ZDHHCs). The modification increases membrane association, protein-protein interactions, and subcellular localization. S-palmitoylation is also reversible, with depalmitoylation catalyzed by acyl-protein thioesterases (APTs), allowing for regulatory control of protein function.

S-palmitoylation aberrations have been associated with cancer development, immune escape, and drug resistance. Dysregulation of ZDHHC enzymes may result in changed palmitoylation patterns of oncogenic proteins, immune checkpoint regulators, and drug-resistance mediators, thus influencing tumor behavior and immune responses.

S-Palmitoylation in Tumor Immunity

The tumor microenvironment (TME) plays a critical role in shaping immune responses. Immune cells within the TME, including T cells, macrophages, and natural killer (NK) cells, rely on proper S-palmitoylation for optimal function. Key immunoregulatory proteins affected by S-palmitoylation include:

1. Immune Checkpoint Proteins

   • Programmed cell death protein 1 (PD-1) and its ligand PD-L1 undergo S-palmitoylation, influencing their stability and localization.

   • Increased PD-L1 palmitoylation enhances its expression on cancer cells, promoting immune evasion.

   • Targeting PD-L1 palmitoylation has been proposed as a strategy to improve the efficacy of immune checkpoint inhibitors (ICIs).

2. T Cell Activation and Function

   • S-palmitoylation regulates the trafficking and clustering of T cell receptors (TCRs), modulating T cell activation.

   • Altered palmitoylation of signaling molecules like Lck and LAT affects T cell-mediated cytotoxicity against tumors.

3. Macrophage Polarization

   • Palmitoylation of key macrophage signaling proteins influences the balance between pro-inflammatory (M1) and anti-inflammatory (M2) macrophages.

   • M2 macrophages contribute to tumor progression by secreting immunosuppressive cytokines and targeting their palmitoylation pathways could reprogram them into an antitumor phenotype.

Targeting S-Palmitoylation for Cancer Therapy

Given its pivotal role in cancer progression and immune regulation, S-palmitoylation is an attractive target for therapeutic intervention. Several strategies are being explored:

1. ZDHHC Inhibitors

   • Small-molecule inhibitors targeting specific ZDHHC enzymes have been developed to disrupt the palmitoylation of oncogenic proteins.

   • Inhibition of ZDHHC3 and ZDHHC9 has shown promise in preclinical models of colorectal and lung cancer.

2. Depalmitoylation Enhancers

   • Pharmacological activation of APTs can lead to the removal of palmitate groups from oncogenic proteins, impairing their function.

   • APT1 and APT2 activators are being investigated for their potential to suppress tumor growth.

3. Combination Therapies with Immune Checkpoint Inhibitors

   • Disrupting S-palmitoylation of PD-L1 can enhance immune system recognition and improve responses to checkpoint blockade therapy.

   • Preclinical studies have demonstrated synergistic effects between palmitoylation inhibitors and ICIs in melanoma and lung cancer models.

4. Palmitoylation-Targeting RNA Therapies

   • Emerging RNA-based therapeutics aim to selectively silence palmitoylation-related genes in tumors.

   • RNA interference (RNAi) strategies targeting ZDHHC overexpression have shown potential in glioblastoma and breast cancer models.

Challenges and Future Directions

While targeting S-palmitoylation holds significant promise, several challenges remain:

• Selectivity and Off-Target Effects: Many ZDHHC enzymes have overlapping substrates, making it difficult to achieve specificity in targeting oncogenic pathways without affecting normal cellular functions.

• Delivery Mechanisms: Effective drug delivery remains a challenge, particularly for RNA-based and small-molecule therapies targeting palmitoylation pathways.

• Biomarker Development: Identifying reliable biomarkers for palmitoylation activity in tumors will be essential for patient stratification and treatment monitoring.

• Resistance Mechanisms: Cancer cells may develop compensatory mechanisms to bypass palmitoylation inhibition, necessitating combination approaches.

Future research should focus on refining drug specificity, optimizing delivery systems, and conducting clinical trials to validate palmitoylation-targeted therapies in cancer patients. Integrating computational modeling, CRISPR-based gene editing, and high-throughput screening can further accelerate the development of effective therapeutics.

Conclusion

Protein S-palmitoylation is becoming an important modulator of tumor immunity and resistance to therapy. Progress in its function in oncogenesis and immune escape has created new opportunities for targeted therapies. Through the use of small-molecule inhibitors, RNA-based approaches, and combination with current immunotherapies, scientists are opening the door to new cancer treatments. As studies continue, targeting S-palmitoylation could provide a potent approach to boost antitumor immunity and enhance clinical outcomes in cancer patients.

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