Why do some viruses and cancer cells survive the sophisticated immune system?

Tolulope Oladimeji

The immune system is the body’s primary defense against disease and foreign agents. It operates across multiple layers, from the physical barrier of the skin to highly specialized adaptive immune cells such as T and B lymphocytes. The immune system is broadly divided into the innate and adaptive immune systems, which work together to mount coordinated responses against pathogens. 

Together, these systems comprise organs (primary lymphoid organs such as the bone marrow and thymus, and secondary lymphoid organs including lymph nodes, spleen, and mucosa-associated lymphoid tissue [MALT]), cells (neutrophils, monocytes, dendritic cells, macrophages, natural killer cells, B cells, and T cells), and humoral components (antibodies, cytokines, and chemokines) (1). 

Despite this highly coordinated defense network, foreign agents such as viruses and abnormal proliferating cells, commonly referred to as cancer or tumor cells, can evade immune detection. In some cases, they can even induce a state of immunosuppression, in which the immune system becomes less effective not only against the original threat but also against other pathogens it would normally eliminate. This article explores how viruses and cancer cells achieve immune evasion. 

Virus and cancer immune evasion can be broadly explained through four major mechanisms (2): 

● Tumor/Virus-induced immunosuppressive signaling 

● Immune checkpoint dysregulation and T-cell exhaustion 

● Tumor microenvironment and tissue-level immune exclusion 

● Antigen presentation and immune recognition escape 

Tumor/Virus-Induced Immunosuppressive Signaling 

Viruses and cancer cells often manipulate immune signaling by secreting inflammatory soluble mediators such as cytokines and chemokines, frequently at abnormally high levels compared to healthy cells. 

During the acute phase of Human Immunodeficiency Virus (HIV) infection, widespread immune activation leads to the release of cytokines such as interleukin-10 (IL-10), transforming growth factor-beta (TGF-β), and interferon-α (IFN-α), contributing to a cytokine storm (3). These cytokines drive further immune activation, particularly of CD4⁺ T cells, which serve as primary

targets for HIV infection. As infection progresses, depletion and dysfunction of CD4⁺ T cells impair the activation of B cells, reducing antibody production and weakening adaptive immunity (4). 

Similarly, tumor cells secrete immunosuppressive cytokines such as IL-10 and TGF-β and recruit suppressive immune populations, including regulatory T cells (Tregs), M2 tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs). These collectively contribute to systemic immune suppression and tumor immune escape. 

Immune Checkpoint Dysregulation and T-cell Exhaustion 

The immune system uses immune checkpoints to regulate T-cell activation and prevent excessive immune responses that could damage healthy tissue. However, tumor cells often hijack these pathways to suppress immune activity. 

Cancer cells frequently upregulate checkpoint ligands such as PD-L1 (programmed death-ligand 1) and influence pathways such as CTLA-4 signaling, thereby inhibiting T-cell activation and proliferation (6,7). This can be compared to a series of security checkpoints that prevent effective progression, ultimately limiting immune responses against the tumor. 

PD-L1 plays a key role in maintaining immune homeostasis by binding to PD-1 (programmed death-1, CD279) on activated T cells. This interaction transmits inhibitory signals that reduce T-cell proliferation and cytokine production. While this mechanism is essential for preventing

autoimmunity under normal conditions, its overactivation during cancer or chronic infection leads to profound suppression of T-cell function and impaired immune clearance (2). 

Tumor Microenvironment and Tissue-Level Immune Exclusion 

A defining feature of many tumors is their ability to reshape the surrounding tissue environment to support immune evasion and survival. Within the tumor microenvironment, cancer cells secrete immunomodulatory cytokines such as IL-10, which recruit immune cells like macrophages and polarize them into an M2-like phenotype, commonly referred to as tumor-associated macrophages (TAMs). 

M1 and M2 macrophages represent functional states of innate immune cells. M1 macrophages are classically activated and promote pathogen clearance by engulfing pathogens and presenting pathogen-associated molecular patterns (PAMPs) to T cells, thereby activating adaptive immunity. In contrast, M2 macrophages promote tissue repair and suppress inflammation through secretion of IL-10 and TGF-β, cytokines that are also produced within the tumor microenvironment. 

Once reprogrammed into M2-TAMs, these macrophages support tumor progression by promoting tissue remodeling, angiogenesis, and metastasis (8). In addition, metabolic reprogramming within tumor cells, particularly increased glycolysis, leads to lactate accumulation, which suppresses the cytotoxic activity of T cells and natural killer (NK) cells (9). 

In contrast, viruses do not typically create a structured physical tumor-like microenvironment. Instead, they induce functional immune exhaustion through persistent antigen exposure and chronic inflammation. For example, chronic viral infections such as hepatitis can lead to fibrosis, while HIV infection is associated with immune dysfunction within lymphoid tissues, contributing to long-term immune exhaustion and impaired immune surveillance. 

Antigen Presentation and Immune Recognition Escape 

Effective immune responses depend on antigen presentation and recognition. Antigens are processed and presented by major histocompatibility complex (MHC) molecules to T cells, linking innate and adaptive immunity. 

MHC class I molecules present intracellular antigens to CD8⁺ cytotoxic T lymphocytes, enabling the immune system to identify and eliminate infected or malignant cells. However, both viruses

and cancer cells can evade immune detection by downregulating MHC class I expression, thereby preventing antigen presentation. 

This evasion strategy is achieved through genetic mutations, epigenetic regulation, and interference with antigen processing pathways. By reducing MHC class I expression, infected or malignant cells become less visible to cytotoxic T cells, allowing continued survival and proliferation. 

Clinical Implications 

These immune evasion mechanisms are actively targeted in modern therapeutic development for both cancer and viral diseases. 

For example, CAR-T cell therapy utilizes genetically engineered patient T cells expressing chimeric antigen receptors (CARs), enabling them to recognize tumor antigens independently of MHC class I presentation. This approach is particularly useful in cancers where MHC downregulation limits immune recognition (10). 

Immune checkpoint inhibitors such as ipilimumab and durvalumab are FDA-approved therapies used in the treatment of several malignancies, including lung and kidney cancers (11). These therapies function by blocking inhibitory immune pathways, thereby restoring T-cell activity against tumors. 

In addition, next-generation approaches such as personalized mRNA cancer vaccines and engineered cellular therapies are currently under active investigation. These strategies aim to enhance immune recognition, reverse immune suppression, and improve long-term disease control. Collectively, these advances suggest a future in which both cancer and chronic viral infections may become increasingly manageable or preventable. 

REFERENCES 

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Assessed and Endorsed by the MedReport Medical Review Board