VT-Cell Exhaustion vs. Activation: Implications for Immunotherapy

Bein Lui

doi:10.35841/aajcit-8.2.257

Perspective - Journal of Cancer Immunology & Therapy (2025) Volume 8, Issue 2

VT-Cell Exhaustion vs. Activation: Implications for Immunotherapy

Bein Lui ^*

College of Guangdong Ocean University, China

*Corresponding Author:: Bein Lui
College of Guangdong Ocean University, College of Guangdong Ocean University, China
E-mail: bein.l@gmail.com

Received: 03-Apr -2025, Manuscript No. AAJCIT-25-163912; Editor assigned: 04-Apr-2025, PreQC No. AAJCIT-25-163912 (PQ); Reviewed:18-Apr-2025, QC No. AAJCIT-25-163912; Revised:23-Apr-2025, Manuscript No. AAJCIT-25-163912 (R); Published:28-Apr-2025, DOI:10.35841/aajcit-8.2.257

Citation: Lui B. T-cell exhaustion vs. Activation: Implications for immunotherapy. J Cancer Immunol Ther. 2025;8(2):257

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Introduction

T cells play a critical role in the immune system’s ability to fight infections, cancers, and other diseases. However, their effectiveness can be compromised by two opposing phenomena: activation and exhaustion. While T-cell activation is essential for robust immune responses, prolonged stimulation can lead to exhaustion, characterized by reduced functionality and an inability to control disease progression [1].

In the context of immunotherapy, understanding the balance between T-cell activation and exhaustion is crucial. This article explores these mechanisms, their impact on disease treatment, and how modern immunotherapies aim to restore optimal T-cell function [2].

T-cell activation occurs when antigen-presenting cells (APCs) present a foreign antigen to a naïve T cell via the major histocompatibility complex (MHC). This process involves three key signals: T-cell receptors (TCRs) bind to antigen-MHC complexes on APCs. Co-stimulatory molecules like CD28 bind to their ligands (e.g., CD80/CD86) on APCs, enhancing activation [3].

Cytokines such as IL-2 promote clonal expansion and effector functions. Once activated, T cells proliferate and differentiate into cytotoxic (CD8+) or helper (CD4+) T cells. Cytotoxic T cells directly kill infected or malignant cells, while helper T cells coordinate immune responses [4].

T-cell activation is essential in tumor immunity, where activated T cells recognize and destroy cancer cells. Similarly, in viral infections, such as HIV or COVID-19, a strong T-cell response is necessary for viral clearance. However, prolonged or chronic stimulation can lead to T-cell exhaustion, a major barrier in treating persistent infections and cancers [5].

T-cell exhaustion occurs when prolonged antigen exposure leads to diminished function. This state is characterized by: Autoimmune diseases, where persistent self-antigen stimulation can lead to dysregulation. For example, in chronic viral infections, exhausted T cells lose their ability to produce IL-2, TNF-α, and IFN-γ, weakening the immune response [6].

Checkpoint inhibitors (CPIs) aim to reverse T-cell exhaustion by blocking inhibitory receptors: Pembrolizumab and nivolumab prevent PD-1 from binding to PD-L1, restoring T-cell function. Ipilimumab blocks CTLA-4, promoting early-stage T-cell activation [7].

These therapies have revolutionized cancer treatment, particularly for melanoma, lung cancer, and Hodgkin’s lymphoma. Chimeric antigen receptor (CAR) T-cell therapy genetically engineers T cells to recognize specific cancer antigens, bypassing exhaustion pathways. FDA-approved CAR-T therapies like tisagenlecleucel (Kymriah) have shown remarkable success in B-cell malignancies [8].

Recent studies highlight the importance of metabolic reprogramming in reversing exhaustion. Approaches include: Enhancing mitochondrial function to improve T-cell persistence. Targeting the mTOR pathway to modulate T-cell energy metabolism [9].

Checkpoint blockade can lead to immune-related adverse events (irAEs), where the immune system attacks healthy tissues. Understanding the balance between activation and autoimmunity is crucial. While immunotherapies are well-established in oncology, research is exploring T-cell modulation in chronic infections (e.g., HIV cure strategies) and autoimmune diseases (e.g., MS, rheumatoid arthritis). Combining CPIs with other therapies, such as cytokine therapy, cancer vaccines, or metabolic modulators, enhances efficacy and prevents resistance. For example, IL-2 and IL-12 therapies boost T-cell survival in exhausted states [10].