The Abscopal Effect: How Treating One Tumor Can Heal the Whole Body 

• Abscopal effect is a known but rare phenomenon that occurs when using one or more therapies (radiotherapy, local hyperthermia, etc.) to eliminate a tumor in one site results in the elimination of tumors all over the body without directly treating them.
• The elimination of tumors throughout the body can only result from  activation of the immune system so that it is able to identify and eliminate CFC cells (cancer cells) wherever they may be located in the body.
• This article describes the mechanisms underlying immune activation, which conditions within the body and in the tumor microenvironment suppress it, and how these conditions can be reversed with an integrative treatment approach

True healing from CFCs (cancer) and preventing its return requires a competent, fully functional immune system with the ability to recognize and eliminate CFCs (cancer cells) as they arise and to prevent their initiation. However, CFCs elmploy multiple strategies to suppress, manipulate and become invisible to the immune system. For example, CFCs “disguise” themselves by removing cellular components from their surface that would normally trigger an immune response. Furthermore, the immediate environment around a tumor, being highly acidic and hypoxic (low in oxygen), known as the tumor microenvironment (TME), modifies immune cells such that they either become inactivated or actually start “working” for the tumor by producing chemicals (cytokines) that protect the tumor and block immune invasion. This situation of immune suppression and usurpation allows CFCs to grow and spread unchecked. 

Could there be a way to reawaken the immune system and direct its attack against CFCs? Actually, there are several ways in which this occurs naturally, such as having a sustained high fever, however research has uncovered another phenomenon called the abscopal effect. In 1953, Robert H.  Mole, a British radiobiologist and clinical pathologist published his findings with mice where non-irradiated tumors in a different location than the treated tumor also shrunk. He coined the term “abscopal” from the Latin “ab” (away from) and “scopus” (target).

Initially thought to be rare, it was later found that this effect requires an intact immune system, hence somehow the suppressed immunity had been reawakened. 

However, it was the 2011 FDA approval of the first checkpoint inhibitor, ipilimumab (anti-CTLA-4) and the subsequent use of this and other such agents in conjunction with radiotherapy that served as the needed impetus for a resurgence of research regarding this phenomenon. 

The Mechanism Behind the Abscopal Effect 

The mechanism by which local tumor therapy triggers a whole-body immune response against CFCs involves breaking down CFCs and making them visible to the immune system. This process, called necrotic cell death, releases hidden danger signals – damage-associated molecular patterns (DAMPs), fragments of DNA, heat shock proteins and other components into the environment that alert the immune system to the presence of CFCs. 

Once these danger signals are detected, immune cells start to act:

• Dendritic cells and macrophages collect tumor fragments or antigens and carry them to the lymph nodes, where they “train” T cells to recognize and attack CFCs.  
• Natural killer (NK) cells are activated. These cells monitor the body detecting and destroying CFCs directly without having to recognize specific markers (as T cells do).
• T cells develop a memory of CFCs, providing long-term protection against the CFCs growing back.

Treatments That Can Trigger the Abscopal Effect  

• Thermal Ablation: Using Heat or Cold to Destroy Tumors 

Thermal ablation methods destroy tumors with extremely high or low temperatures. All ablation methods have been documented to create an abscopal effect, although with varying strengths.

• Most Effective
  • Cryoablation (freezing tumors with argon gas) and Radiofrequency Ablation (heating tumors with electrical energy) cause widespread necrosis, releasing tumor fragments and increasing immune activating cytokines such as IL-6 and TNF- α

• Less Effective

• • Microwave Ablation (heating tumors with electromagnetic energy) and High-Intensity Focused Ultrasound (heating tumors with ultrasound) also trigger an immune response but to a lesser degree.

The challenge with thermal ablation is that the extreme temperatures required for necrotic cell death are not achieved throughout the entire tumor. This is because nearby blood flow carries heat away from the tumor resulting in milder temperatures and leaving the edges of the tumor incompletely destroyed. Some cells nearby margins die through apoptosis that goes unnoticed by the immune system or even suppress its response. Apoptosis is a controlled, more “silent” form of cell death where cellular components are packed and cleaned undetected by the immune system. 

• Histotripsy: The Most Powerful Abscopal Effect

Histotripsy is a non-thermal ablation method that destroys tumors through a process called acoustic cavitation where short, high-pressure ultrasound bursts generate tiny gas bubbles. These bubbles expand and collapse rapidly, shattering cancer cells with intense mechanical force. In human clinical trials, this treatment has been found to induce the strongest abscopal effect to date.

Unlike thermal-based ablation methods, histotripsy:

• • Destroys the entire tumor mass through necrosis
  • Releases danger signals without damaging them with heat, keeping them in easily recognizable form for the immune system 
  • Spares healthy tissue from damage, minimizing side effects

• Local Hyperthermia

In local hyperthermia heat is applied directly to a tumor. Raising tumor temperature to 41-45 °C damages CFCs, preventing them from repairing themselves. As they break apart, they release danger signals such as heat shock proteins that help the immune system recognize and attack CFCs. 

1. 1. Radiation Therapy

Ionizing radiation kills CFCs, making them release immune-stimulating danger signals. Although radiation therapy is the first treatment found to trigger an abscopal effect, its effectiveness is limited by its deleterious effects on immune cells. If nearby lymph nodes, which are crucial sites for CFC recognition, are included in the radiation field, immune activation is weakened, reducing the abscopal effect.

How to Maximize the Abscopal Effect

Although documented in all the above treatments, an abscopal effect – an immune response induced by local tumor removal – strong enough to eliminate metastatic CFCs is still a rare event. The main reason is that, regardless of the CFCs exposed, the resulting immune-stimulating effect is temporary and unpredictable because of CFCs’ continuous attempts to suppress the immune system. 

Key Barriers for the Abscopal Effect to Occur:

• Poor Tumor Accessibility

Tumors suffer from weak blood circulation due to growth of excessive but chaotic and poorly formed blood vessels. This creates a physical barrier for immune cells (and therapeutic agents) to access the tumor. 

• Immune Suppression

Even when immune cells reach the tumor site, the tumor’s low-oxygen (hypoxic) and acidic environment inactivates the immune cells, making them unable to attack the tumor or even transforms them into tumor supporting immune cells 

Fortunately, there are supporting strategies that can be combined with local tumor treatments to overcome these obstacles and unlock the full potential of the abscopal effect.

Enhancing Strategies 

• Whole-Body Hyperthermia 

In whole-body hyperthermia, the temperature of the entire body is elevated to (38-41 °C) for several hours. This treatment has several benefits:

• • Activates the immune system, mimicking a natural fever response
  • Increases blood flow to the tumor, which both facilitates the entry of immune cells and helps them remain active in a better oxygenated tumor
  • Induces CFCs to release heat shock proteins that alert the immune system

When combined with radiation or tumor ablation, hyperthermia has been shown to improve treatment outcomes by amplifying necrotic cell death and immune activation. 

• Physical Movement 

Physical activity has profound effects on CFCs:

• • Improves blood flow, delivering more oxygen and immune cells to tumors
  • Increases the production of natural killer (NK) cells and CD8+ T cells, supercharging the immune system’s ability to recognize and destroy CFCs 
  • Triggers muscles to release cytokines such as IL-6, which guide T cells to target the tumor
  • Regular exercise can also repair the abnormal tumor blood vessels, leading to lasting improvements in tumor blood flow and oxygenation, allowing long-term access for immune cells as well as therapeutic agents

The impact of exercise on the abscopal effect has been demonstrated in animal studies where a tumor that is unresponsive to immunotherapy due to absence immune cells (called a cold tumor) has been converted to a responsive (hot tumor – infiltrated by immune cells) through exercise practice.

• Reducing Tumor Acidity

CFCs produce excess lactic acid in their metabolism, making the tumor microenvironment too acidic for immune cells to function properly. Animal and human studies show that neutralizing the acidity with bicarbonate (injected directly into the tumor) before tumor ablation can enhance the immune response and reduce metastasis. A more natural way to reduce acidity is exercise, which has been shown in animal studies to remove lactic acid from tumors through increased blood flow.

• Immunotherapies

To boost the abscopal effect, local tumor treatment can be combined with immune-enhancing therapies, including:

• GM-CSF injections: A therapy that increases immune cell activity.  For example, one clinical trial combined local radiotherapy with subcutaneous GM-CSF injections in people with metastatic solid tumors. An abscopal response – tumor shrinkage outside the radiation field was observed in 30% of individuals.
• Dendritic cell therapy: Injecting dendritic cells (immune cells that train T cells to recognize CFCs) into tumors after radiation treatment has led to increased infiltration of T cells to tumors, tumor shrinkage and prevented CFCs from growing back in clinical trials.

• Managing Stress 

Addressing psychological stress (anxiety, fear, depression etc.) is more than improving quality of life – it directly influences the immune system’s ability to detect and destroy CFCs. A research field of psychoneuroimmunology has found several mechanisms behind it. One is that chronic stress shuts down the immune system by releasing stress hormones such as norepinephrine and cortisol which inactivate T-cells and natural killer cells – main immune cells for eliminating tumors. Studies on mice have demonstrated the impact of chronic stress on the abscopal effect. In one study treating a primary tumor with radiation also slowed the growth of unirradiated tumors. However, stressing mice chronically with cool housing temperatures greatly suppressed the immune system ability to control tumor growth, particularly outside the radiation field. 

In humans the use of β-blockers (primarily for cardiovascular conditions), which prevents the effects of stress hormones, has been linked to decreased metastases and improved survival in people undergoing radiotherapy and immunotherapy. 

Practices such as meditation, deep breathing, and relaxation techniques have been shown to both support mental health and strengthen the immune system’s function.

• Gut Microbiome

Gut microbiome – the vast community of microbes in the intestines significantly influence the immune system’s development and function. Its impact is so profound that the composition of microbiome has been shown to determine how well people respond to immunotherapy. For optimal immune function microbial diversity appears to be essential. For example, a study on people with cervical CFCs found that those with more diverse gut microbiomes at the start of chemoradiotherapy treatment had higher survival rates. A diverse microbiome led to greater tumor infiltration of CD4+ T cells – essential immune cells in the body’s defense against CFCs. 

Although the gut microbiome is extremely complex, some specific species have been identified to strongly modify the immune response:

Bacteria that boost the immune response

1. Bacteroides thetaiotaomicron and Bacteroides fragilis 

• Reduce suppressive immune cells (unable to eliminate CFCs) regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment
• Increase Th1 cells – immune cells capable of eliminating CFCs

1. Akkermansia muciniphila 

• Stimulates IFN-gamma production, a key immune cytokine for attacking tumors
• Produces beneficial short chain fatty acids (SCFAs) that activate CD8+ T cells 

• Bifidobacterium

• Increases dendritic cells, which help activate T cells
• Improves T cell infiltration into tumors
• Enhances IFN-gamma production for a stronger immune attack

Studies show that people with more Bacteroides, Akkermansia and Bifidobacterium in their gut tend to have better outcomes with immunotherapy. In fact, supplementing with Akkermansia muciniphila has been shown to restore the effectiveness of immunotherapy in those who initially did not respond.

Bacteria that may hinder immune response

Certain species, on the other hand, can be harmful by causing chronic inflammation, suppressing the immune system and even migrating to the tumor directly supporting its growth.

• Escherichia/Shigella: Linked to diarrheal disease and weakened immune function

How to Improve the Gut Microbiome for Better Immune Response

While the composition of gut microbiome is strongly influenced by early development and childhood, certain lifestyle choices can later improve its diversity: 

• • Eating more plant-based foods – Especially foods rich in polyphenols such as cranberries, green tea, apples, pomegranate, rhubarb and even white kidney beans encourages growth of beneficial bacteria such as Akkermansia muciniphila
  • Spending time in nature and rural areas – Exposes the body to a wider diversity of natural microbial ecosystems which can increase the diversity of microbial species in the gut 

• • Regular Exercise 

• • Avoiding unnecessary antibiotics

• • Probiotic supplements 

Is local tumor treatment always necessary to trigger a whole-body immune response against CFCs? 

No. Although the tumor ablation methods described above can produce large amounts of dead CFC fragments that activate the immune system, healing from metastatic CFCs is possible without them. The enhancing strategies discussed support the immune system in recognizing and eliminating CFCs from the whole body. The addition of non-toxic metabolic therapies (Intravenous High Dose Vitamin C, Curcumin, Quercetin etc.) will further accelerate the process by selectively killing CFCs and reducing tumor burden.

In short, to take full advantage of local tumor treatment and maximize the abscopal effect or systemic immune response against distant metastases, CFC treatment requires a full body approach which includes therapies and lifestyle choices that improve blood flow, modify the tumor microenvironment and enhance immunity. By combining these strategies, targeting one tumor can be turned into a powerful whole-body healing.

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