The immune system’s primary function is constant immune surveillance, continually scanning the body for abnormal cells. Specialized immune cells, such as cytotoxic T cells and Natural Killer (NK) cells, identify and destroy cells that display markers of damage or mutation, effectively preventing disease development. Cancer arises when this intricate surveillance mechanism fails to recognize or eliminate transformed cells, allowing them to proliferate unchecked. The complexity of the cancer-immune relationship is defined by the cancer cell’s ability to manipulate the host’s defense mechanisms, resulting in a compromised immune state that aids tumor growth and progression.
Mechanisms of Immune Evasion
The most fundamental way cancer affects the immune system is by developing strategies to become invisible, a process termed immune evasion. Cancer cells achieve this by losing or downregulating the specific molecules that mark them as foreign, which prevents immune recognition. These unique identifiers, known as tumor antigens, are mutated proteins or abnormal fragments displayed on the cell surface. Tumors that stop producing these antigens are no longer targets for the immune system, allowing them to escape destruction.
This lack of recognition is frequently linked to alterations in Major Histocompatibility Complex (MHC) Class I molecules. Normal cells use MHC Class I molecules to present internal protein fragments, including abnormal tumor antigens, on their surface for T-cells to inspect. Cancer cells often reduce or completely stop the expression of these MHC I molecules, removing the display case for their abnormal contents. By eliminating the presentation of tumor antigens, the cancer cell prevents cytotoxic T-cells (CD8+ T-cells) from recognizing them as threats, thereby avoiding an immune response.
Active Suppression of Immune Response
Distinct from hiding, cancer actively disables immune cells that have already entered the tumor environment through active suppression. This suppression is centered in the tumor microenvironment (TME), a complex mixture of cancer cells, blood vessels, and various immune and structural cells. Within the TME, the tumor releases inhibitory signals that paralyze the function of anti-tumor immune cells.
A major mechanism of this active suppression involves immune checkpoint molecules, which are proteins on the surface of immune cells and cancer cells that act like “off” switches. For example, tumor cells often express high levels of the protein PD-L1, which binds to the PD-1 receptor on T-cells. This interaction delivers an inhibitory signal that prevents the T-cell from attacking the cancer cell, rendering the immune response ineffective. The TME is also heavily populated by suppressive immune cell types that the tumor recruits and activates.
One such cell type is the Regulatory T-cell (Treg), which primarily works to maintain immune tolerance. In cancer, Tregs accumulate within the tumor and actively suppress the activity of other anti-tumor T-cells by releasing inhibitory molecules like IL-10 and TGF-\(\beta\). Another powerful suppressive population is the Myeloid-Derived Suppressor Cell (MDSC), which expands significantly in cancer patients. MDSCs suppress T-cell function through multiple mechanisms, including depleting necessary nutrients and expressing high levels of immune checkpoint ligands, ensuring that any immune cell entering the tumor is quickly neutralized.
The Paradoxical Role of Inflammation
While acute inflammation fights infection, chronic, low-grade inflammation within the TME can paradoxically support cancer growth and progression. This sustained inflammatory state is often initiated by the tumor itself and involves the recruitment of immune cells that become co-opted to serve the cancer’s needs.
A prime example of this co-option involves Tumor-Associated Macrophages (TAMs), a type of immune cell that accumulates in the TME. Instead of destroying the cancer, these TAMs are reprogrammed to an “M2-like” phenotype, where they function more like wound-healing cells than immune fighters. These M2-like TAMs release growth factors and enzymes that promote tumor cell proliferation and the breakdown of surrounding tissue, facilitating invasion and metastasis.
Furthermore, TAMs and other inflammatory cells contribute significantly to angiogenesis, the process of forming new blood vessels. They secrete proangiogenic factors, such as Vascular Endothelial Growth Factor (VEGF), which stimulates the development of a blood supply to nourish the rapidly growing tumor. By promoting new vessel formation and releasing factors that encourage cell survival, the chronic inflammatory environment acts as a supportive scaffold, accelerating tumor growth and aiding its spread.
Systemic Effects on Immune Health
Beyond the local effects within the tumor, cancer induces systemic changes that severely compromise overall immune health. The sustained presence of the tumor and its associated inflammatory factors leads to cancer-induced immunosuppression throughout the body. This generalized weakening significantly increases a patient’s susceptibility to infections.
The chronic inflammatory signaling, driven by cytokines like Tumor Necrosis Factor-alpha (TNF-\(\alpha\)) and Interleukin-6 (IL-6), plays a direct role in cancer cachexia, or wasting syndrome. These inflammatory molecules disrupt normal metabolic homeostasis, leading to the breakdown of muscle and fat tissue. This is a debilitating condition affecting many advanced cancer patients. TNF-\(\alpha\) promotes muscle protein degradation and contributes to loss of appetite.
In addition to these functional deficits, the cancer burden and its treatments often lead to cytopenia, a reduction in the number of circulating white blood cells. This decrease affects various immune populations, including lymphocytes, leaving the patient with fewer cells available to mount an effective defense against pathogens. This combination of systemic inflammation, metabolic disruption, and reduced immune cell counts creates profound immune dysregulation that contributes to poor response to therapies and increased mortality.