Radiation therapy is a treatment for cancer that uses high-energy rays to destroy malignant cells. The body’s immune system is its natural defense force, tasked with eliminating threats, including cancerous cells. While once viewed as primarily suppressive, research reveals a complex dynamic where radiation can also stimulate the immune response against cancer.
Radiation’s Suppressive Impact on Immunity
Radiation therapy, while aimed at tumors, can have unintended consequences for the immune system. The high-energy beams affect rapidly dividing cells, a hallmark of cancer. Unfortunately, many active cells in the immune system also share this characteristic, making them susceptible to collateral damage and leading to immunosuppressive effects.
Among the most vulnerable are lymphocytes, a type of white blood cell that includes T-cells and B-cells, which are central to adaptive immunity. These cells circulate throughout the body. When the radiation field includes major blood vessels or lymph nodes, these circulating cells can be destroyed, leading to a condition known as lymphopenia—a reduction in lymphocytes. T-cells are highly radiosensitive, and their depletion weakens the body’s ability to mount a specific attack against cancer cells.
Another mechanism of suppression involves the bone marrow, the body’s factory for producing all blood cells. If a large volume of active bone marrow falls within the high-dose radiation field, its ability to generate new immune cells can be substantially impaired. This can lead to broader immune suppression, affecting not just lymphocytes but also other cells like neutrophils and monocytes. This compromises the body’s defense capabilities and can increase susceptibility to infections.
The Immune-Activating Potential of Radiation
Paradoxically, the same destructive force that can suppress the immune system can also awaken it. While damaging cancer cells, radiation triggers a specific type of cellular demise known as immunogenic cell death (ICD). This process turns the treated tumor into a beacon for the immune system, transforming it into a recognizable target. The effects are primarily localized to the irradiated tumor microenvironment.
When radiation causes cancer cells to die in this immunogenic way, they release signals that function as a distress call. These signals include molecules called damage-associated molecular patterns (DAMPs), such as high-mobility group box 1 (HMGB1) and ATP. These molecules are spilled from the dying cells, alerting and activating specialized immune cells called antigen-presenting cells (APCs), particularly dendritic cells.
Simultaneously, the dying cancer cells release tumor-specific antigens, which are proteins unique to the cancer. The activated dendritic cells act like sentinels, engulfing these newly exposed antigens and processing them. They then present these antigens on their surface, effectively showing the immune system what the cancer “looks like.” This process primes the dendritic cells to initiate a targeted adaptive immune response.
The Abscopal Effect Explained
The localized immune activation within a treated tumor can sometimes lead to a systemic phenomenon known as the abscopal effect. This term describes the regression of metastatic tumors in parts of the body that were not targeted by radiation. This rare occurrence is now recognized as a radiation-induced, system-wide anti-tumor immune response.
The mechanism behind the abscopal effect is a direct extension of immunogenic cell death. Once dendritic cells are activated at the irradiated tumor site and have processed the tumor antigens, they travel to nearby lymph nodes. In the lymph nodes, these APCs present the tumor antigens to naive T-cells, training them to recognize and target those cancer cells. This process creates an “in-situ vaccine,” using the irradiated tumor as the source of antigens.
These newly educated cytotoxic T-cells then enter the general circulation. They function as a specialized patrol, traveling throughout the body to seek out and destroy other cancer cells that bear the same antigens. When these T-cells find metastatic tumors in distant organs—such as the lungs or liver—they infiltrate these sites and attack, causing them to shrink or disappear.
Combining Radiation with Immunotherapy
The understanding that radiation can stimulate an anti-tumor immune response has led to combining it with immunotherapy. This strategy creates a synergistic effect that is more powerful than either treatment alone. The primary partners for radiation in this approach are a class of immunotherapy drugs known as immune checkpoint inhibitors.
The immune system has natural “brakes,” or checkpoints, to prevent it from becoming overactive. Cancer cells often exploit these checkpoints to evade destruction. They can express proteins on their surface, such as PD-L1, that press the brake pedal on T-cells, shutting down the immune attack. Checkpoint inhibitor drugs work by blocking these signals, “taking the brakes off” the T-cells and restoring their ability to fight cancer.
The synergy arises from a two-step process. First, radiation acts as the primer, inducing immunogenic cell death that releases tumor antigens and calls immune cells to the tumor site. This step makes a previously immunologically “cold” tumor “hot” and recognizable. However, even with this recognition, checkpoint signals can still prevent an effective T-cell assault.
By administering checkpoint inhibitors alongside or after radiation, oncologists can ensure that when T-cells arrive at the tumor, they are empowered to attack. The radiation exposes the target, and the immunotherapy unleashes the soldiers. This combination has been shown to increase response rates in some cancers and makes the abscopal effect more common and pronounced, transforming a localized radiation treatment into a systemic cancer therapy.