Authors: Addison Davis and Annabella Irani Fey
Mentor: Katherine Ferris. Katherine is a doctoral candidate in the Department of Oncology at the University of Oxford.
Abstract
Cancer remains one of the most widespread diseases globally, driven by genetic mutations that disrupt normal cell regulation, leading to uncontrolled proliferation and, in some cases, metastasis. While the immune system plays a crucial role in detecting and eliminating cancerous cells, tumors have evolved sophisticated mechanisms to evade immune responses. This article explores the complex interplay between cancer and immunity, detailing key immune processes such as cytotoxicity, phagocytosis, and antigen presentation. Natural killer cells (NKCs) and cytotoxic T lymphocytes (CTLs) contribute to tumor suppression through apoptosis, yet cancer cells can subvert these defenses by altering immune checkpoints and macrophage signaling. Immunotherapeutic advances, including checkpoint inhibitors, CAR-T cell therapy, and monoclonal antibodies, have emerged as powerful tools in reactivating immune responses against cancer. However, chronic inflammation and angiogenesis can paradoxically support tumor growth by fostering an immune-suppressive microenvironment. Despite these challenges, the immune system remains fundamentally opposed to cancer, with continued research into immune regulation and targeted therapies offering promising advancements in cancer treatment.
Introduction
It is commonly known that cancer is one of the most pervasive diseases in the world, affecting around 20% of the global population [Bray et al., 2024]. At its core, cancer is when abnormal cells divide in an uncontrolled way. Some cancers can gain the ability to spread into other tissues in a process known as metastasis, a detrimental occurrence to the individual. The disease is powered by genetic mutations that cause cells to bypass the body’s regulatory mechanisms. Tumors can be widespread throughout the human body, with examples including carcinoma (epithelial tissue), leukemia (blood cancer), glioma (brain cells), sarcoma (bone) and lymphoma (T and B lymphocytes). Some common treatments includes chemotherapy, hormone and radiation therapy, and in the context of boosting the immune system, immunotherapy. Cancer is a very complex disease, but breakthroughs in research, early detection and treatments have increased survival rates and outcomes. In order to boost immune visibility, checkpoint inhibitors (e.g., anti-PD-1, anti-CTLA-4) and CAR-T cell therapy blocks immune suppression and genetically engineers T-cells to kill cancer and specifically target tumour antigens [Cesano et al., 2025]. Additionally, there are cancer vaccines, such as the HPV vaccine, which trains the immune system to recognize and eliminate potentially cancerous or mutated cells.
The harmful mutations that cause cancer do more than simply drive the abnormal growth; they also alter the proteins displayed on the surface of cancer cells, thus creating fragments that the immune system can potentially recognize and actively fight against. Despite this visibility however, cancer often manages to evade immune detection, dramatically complicating efforts to prevent and treat the disease [Jhunjhunwala et al., 2021].
To understand this significant dynamic, is it vital to consider the complexity of the immune system as a whole. The immune system is an interlinked network of cells, tissues and molecules that comprise innate immunity with rapid, non-specific defense and adaptive immunity with highly specific protection. As part of the innate system, macrophages, neutrophil and dendritic cells engulf and digest pathogen in a first line of defense called phagocytosis. An additional outcome to this process is the release of chemical signals (cytokines) that trigger inflammation and angiogenesis (the process of promoting new blood vessel formation), facilitating recruitment of immune cells to the infected tissue. Among these cells are natural killer cells (NKCs) and cytotoxic T cells (CTLs) which belong to the innate and adaptive responses respectively, but both kill infected cells through cytotoxicity. The rest of the adaptive response is carried out by B cells and T helper cells. B cells produce antibodies that coat pathogens to help the immune system identify and phagocytose foreign invaders (bacteria, viruses, etc.) [Dilosa et al., 1991]. They can also bind to the toxins that these pathogens release, helping to neutralize them. T helper cells aid in regulating the magnitude of the immune response, and are important in preventing it from becoming excessive [Eardley et al., 1978]. These cells protect against intemperate inflammation, autoimmunity or chronic disease.
The relationship between cancer and the immune system is extremely nuanced. While immune cells can recognize and destroy early cancerous growths [Dunn et al., 2004], they can also contribute to tumor development primarily by promoting chronic inflammation and supporting blood vessel formation [Coussens and Werb, 2002]. This conflicting nature emphasizes the need for a deeper understanding of the immune system’s interactions with cancer as well as how these occurrences can be controlled, leading to more effective medical treatments.
Literature Review
Cytotoxicity and Cancer
Cytotoxicity is an important part of how the immune system fights cancer. NKCs and CTLs are important because they kill tumor cells by inducing apoptosis. Tumor-infiltrating lymphocytes (TILs), which include CTLs, often lead to better results by directly fighting tumors [Gooden et al., 2011]. However, cancer cells can hide from these defenses. For example, cancer cells can reprogram the genetic makeup of natural killer cells to “convert” them from cytotoxic to a phenotype that ultimately promotes metastasis [Chan et al., 2020].
Additionally, macrophages can release signals to suppress the CTLs crucial for attacking tumor cells. For example, macrophages can release TNFα and IL-10 to increase their own production of PD-L1, which binds to its receptor on CTLs and inhibits their cytotoxic activity [Kuang et al., 2009]. This interaction between PD-L1 and its receptor forms a checkpoint in CTL activation that normally prevents excessive cytotoxicity, but in doing so creates an mechanism by which cancer can evade immune attack. Fortunately, the same mechanism can be targeted therapeutically, with checkpoint inhibitors such as anti-PD-L1 antibodies disrupting the interactions that inhibit cytotoxicity to leave the tumor cells vulnerable to CTLs once again [Akinleye and Rasool, 2019].Macrophages can also suppress CTLs indirectly by producing CCL22 to recruit regulatory T cells, which then mediate suppression of T-cell cytotoxicity [Curiel et al., 2004]. By blocking the activity of CTLs, these macrophage-derived signals avoid cancer cells being destroyed. Understanding how macrophages change and how they affect immune responses is important for developing new treatments that can fight cancer more effectively by regulating these immune cells.
CAR T Cells and Adaptive T Cell Therapy
Chimeric Antigen Receptor (CAR) T cell therapy is a groundbreaking form of adaptive immunotherapy designed to utilize the body’s immune system to target and eliminate cancer cells. In this therapy, a patient’s T cells are genetically modified to express CARs, synthetic receptors that specifically recognize antigens on tumor cells. Once infused back into the patient, these engineered T cells detect and destroy tumor cells through cytotoxicity, inducing apoptosis in their targets. [Miliotou and Papadopoulou, 2018; Kruger et al., 2019] Similarly, natural killer cells (NKCs) are also being explored for cancer therapy due to their innate ability to recognize and kill tumor cells without prior sensitization. Unlike T cells, NKCs do not rely on antigen presentation through major histocompatibility complex (MHC) molecules, making them effective against tumors that are able to avoid MHC-dependent immune responses. [Laskowski et al., 2022] Both therapies ultimately try to fight immune evasion mechanisms employed by cancer, such as downregulating MHC or producing immunosuppressive cytokines. Advances in engineering CAR T cells to improve specificity and reduce side effects, alongside ongoing research into NK cell-based therapy, are positively transforming cancer treatment [Huang et al., 2020; Hu et al., 2019]. These approaches show the potential of adaptive immunity and innate immunity in developing targeted cancer therapies.
Inflammation & Angiogenesis
Inflammation is an important facilitator of tumor progression, partly through the occurrence of angiogenesis—the formation of new blood vessels—which supplies the tumor with important nutrients and oxygen, while also providing pathways for waste removal and spreading of cancer cells [Zhou et al., 2021]. Inflammatory mediators, such as cytokines and chemokines, activate endothelial cells, leading to neovascularization within the tumor area. This new network of blood vessels sustains tumor growth and also offers channels for cancer cells to move into the bloodstream, promoting metastasis. Also, the inflammatory environment can alter vascular permeability, further facilitating tumor cell entry into circulation [García-Román and Zentella-Dehesa, 2013]. Understanding the interactions at the molecular level between inflammation and angiogenesis is very important for developing therapeutic strategies aimed at disrupting these processes that support tumor growth.
Regulating the Immune Response - Macrophage Polarization and the Role of M1 and M2
The immune response can be controlled, and one important aspect of this is how macrophages change to become different types that either fight or help tumors. When macrophages become M1, they help fight tumors by promoting the killing of cancer cells through processes like phagocytosis. On the other hand, when macrophages turn into M2, they support tumor growth by helping cancer cells survive and even stop the immune system from attacking. For example, cancer cells can skew the macrophage population towards the pro-tumor M2 subtype by releasing certain cytokines such as IL-10 [Sica et al., 2008] and activating proteins such as Rubicon, which promotes a phagocytosis pathway that favors M2 polarization [Asare et al., 2020]. This is a form of immune regulation that allows cancer cells to grow.
Cell Proliferation
At the start of an immune response, there are enough cells to detect the foreign signal and fight against it, but there are not enough to eradicate the pathogen entirely, necessitating cell proliferation. This is achieved by two mechanisms. The first one is direct activation of the cell to which the pathogen binds and one of the responses is cell division. Another of the responses is the production of cytokines, some of which promote tumor growth and development. An example of this is IL-6 promoting tumor growth in breast, lung, and colorectal cancers, and can increase proliferation and prevent apoptosis [Radharani et al., 2022; Kumari et al., 2016]. As the cancer cells proliferate, each additional round of DNA replication is an opportunity for additional mutations that may promote tumor growth. An example includes how tumor cells increase TGF-beta production, which triggers IL-17 production in CD8+ T cells, which then causes expression of pro-survival and anti-apoptotic genes in the cancer cells [Nam et al., 2008].
Phagocytosis
Phagocytosis is a process used by certain immune cells such as macrophages, neutrophils and dendritic cells to eradicate harmful particles such as pathogens and infected cells. These cells consume the harmful particles and deconstruct them, ultimately destroying them. This first and foremost removes the pathogens to help eliminate the infection, but also produces small fragments that can be loaded onto MHC class II molecules and presented as antigens to naive T and B cells to activate them.
One way this process is involved in cancer development is through CD47. CD47 on target cells binds to SIRTa on macrophages in order to inhibit phagocytosis. Leukemia cells, for example, upregulate CD47, which increases their ability to invade other tissues without being phagocytosed [Jaiswal et al., 2009]. Additionally with non-Hodgkin lymphoma, the CD47 antibody reduces tumor growth and increases phagocytic index. This antibody has the job of preventing the inhibition of phagocytosis by blocking inhibitory CD47-SIRPa interactions through the variable region of the antibody, and then stimulating it by providing a binding site for FcR, which binds the constant region of the antibody and stimulates phagocytosis. [Advani et al., 2018; Chao et al., 2010]
In contrast to high expression of CD47, low expression allows cancer cells to exploit phagocytes to promote tumor development and expansion. There is sufficient CD47 to impair phagocytosis, but not enough to prevent it completely, resulting in uptake but not degradation of the cancer cell. This allows the engulfed cell to keep its tumorigenic properties while also taking on the properties of the immune cell around it. It has immune markers that create a boundary from the immune system that reinforces the separate immune cell [Chou et al., 2023].
Conclusion - Cancer and the Immune System
Despite the immune system’s occasionally contradictory responses to unhealthy growth, it ultimately functions as a formidable foe to cancer. Through several natural processes, including the detection and destruction of abnormal cells by cytotoxic T cells and the phagocytosis of cancer cells by macrophages, the immune system constantly works to stay healthy and avoid any malignant growths. This process of immune surveillance where immune cells detect and destroy abnormal cells that arise due to mutations heavily protects against the development of cancer. Even in cases where cancer appears to thrive, it is often because the cancer cells have adapted to manipulate or evade immune responses, suggesting that the immune system remains fundamentally hostile to tumor growth. Thus, without a persistent immune response, it is fitting to assume that cancer would be even more rampant and aggressive.
There are several mechanisms by which the immune system combats cancer, as previously mentioned in the article. Phagocytosis and antigen presentation by macrophages and dendritic cells activate T cells, initiating a targeted response. Cytotoxic T-cells induce tumor cell death while natural killer (NK) cells eliminate cancer cells lacking MHC I. B-cells produce antibodies against tumor antigens. Inflammation and tumor suppression enhance immune defenses by recruiting immune cells and releasing pro-inflammatory cytokines like IFN-γ and TNF-α to boost tumor destruction. Angiogenesis inhibition cuts off a tumor’s nutrient supply, restricting its growth. However, while acute inflammation aids immunity, chronic inflammation can promote cancer progression, highlighting the immune system’s dual role. In a general perspective, cancer immunotherapy harnesses these mechanisms in order to strengthen immune response. As mentioned in the introduction and paragraphs, checkpoint inhibitors reactivate T cells, CAR-T cell therapy engineers T cells to attack tumors, and cancer vaccines train the whole system against virus-induced cancers. Monoclonal antibodies tag cancer cells for immune destruction. Despite its power, the immune system faces challenges as tumors evolve to evade detection.
It is important to note that in some instances, this evasion repurposes the immune system to support cancer development. For instance, chronic inflammation is a process that can create an environment that promotes tumor development, as it triggers angiogenesis, forming new blood vessels, creating a steady blood supply for the tumor and enabling its spread. Immune cells release pro-inflammatory cytokines like IL-6 and TNF-α, which drive cell proliferation, survival, and genetic mutations. Inflammatory conditions such as colitis and hepatitis further increase cancer risk by causing tissue damage and creating a tumor-friendly microenvironment. Additionally, the immune system’s wound-healing and angiogenesis processes—normally essential for repair—can be taken over by tumors to secure nutrients and oxygen, with tumor-associated macrophages (TAMs) shifting to a pro-tumor state that supports metastasis.
However, these examples are mere exceptions, and there are far more immune processes that deliberately and effectively work against tumor growth. The fact that cancer needs to develop sophisticated strategies to escape the immune system only reminds individuals of its natural hostility toward deleterious growths. Examples of this include the exploitation of immune checkpoints to deactivate T cells and prevent effective immune attacks and the recruitment of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) to suppress anti-tumor immune responses. These mechanisms highlight the dual nature of the immune system, which, despite its ability to fight cancer, can also unintentionally aid tumor survival, immune evasion, and progression.
This inherent resistance truly offers significant promise for cancer treatment. Immunotherapies, which utilize the body’s natural immune defense processes, have already revolutionized the way some cancers are treated. By further understanding the interactions between cancer and the immune system, researchers and others can continue to develop novel technologies that overall enhance the immune system’s natural capacity to fight this harmful disease. In general, even while cancer finds ways to manipulate the immune process, it is a significant foe to cancer, containing the majority of the processes necessary for protecting the human body from any anomalies.
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