Under normal conditions, cancer cells develop mechanisms to evade immune surveillance by increasing the expression of molecules such as PD-L1 or CD80, which interfere with T cell activation and allow the tumor to go unnoticed. To counter this, therapies such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies block these checkpoints, releasing the “brakes” of the immune system and enhancing its ability to attack cancer.
This shift represents one of the most important advances in modern oncology. However, by removing these regulatory mechanisms, the natural balance of the immune system is also altered. The intense activation of T cells not only promotes the elimination of tumor cells but can also generate an uncontrolled response against healthy tissues. As a result, the immune system may extend its activity beyond the tumor, infiltrating different organs and triggering what are known as immune-related adverse events (IRAE’s).
These autoimmune effects can manifest in virtually any organ in the body, reflecting the ability of the immune system to act systemically once its regulatory mechanisms are lost.
One of the most relevant examples is pneumonitis, an inflammation of the lungs that can compromise respiratory function. The appearance of symptoms such as shortness of breath or changes in breathing requires immediate evaluation. Although a chest X-ray may be a first step, its sensitivity is limited, so a CT scan is usually necessary for an accurate diagnosis. A major clinical challenge is distinguishing pneumonitis from pneumonia, as both may present similar findings but require completely different treatments. In general, pneumonia is associated with fever and elevated white blood cell counts, whereas pneumonitis is not, although this distinction is not always absolute.
Thyroid alterations are also common and may evolve dynamically. Many patients develop hypothyroidism, but in some cases there is an initial phase of hyperthyroidism caused by the sudden release of hormones after damage to the gland. This may generate symptoms such as anxiety, palpitations, and increased heart rate. Over time, thyroid function may decrease, leading to hypothyroidism. In other cases, the immune system stimulates the gland, producing conditions such as Graves’ disease, in which hormone production remains elevated. Due to this variability, evaluation by an endocrinologist is essential.
The liver may also be affected through autoimmune hepatitis, generally detected by elevations in liver enzymes. Mild changes may be monitored, but more significant increases often require treatment with corticosteroids or, in less frequent cases, other immunosuppressive drugs. Regular follow-up allows for timely intervention and helps prevent major complications.
Although these conditions may resemble classical autoimmune diseases, their appearance in the context of immunotherapy is often more abrupt, more extensive, and in many cases less predictable. This is because immune activation is not confined solely to the tumor but may involve multiple tissues simultaneously.
At their core, all these effects share a common origin: excessive activation of the immune system that, while attempting to eliminate cancer, loses part of its ability to discriminate. This phenomenon is not a simple isolated side effect, but rather a direct consequence of the mechanism of action of immunotherapy.
Despite this, it is important to put these effects into context. Many autoimmune events associated with immunotherapy are now predictable, monitorable, and treatable when detected early. Clinical practice includes clear monitoring protocols, multidisciplinary teams, and evidence-based guidelines that allow for timely and effective intervention. For most patients, this translates into a safe management approach in which the benefits of treatment far outweigh the risks.
Figure 1. Immune checkpoint inhibitors release the brakes on the immune system—enhancing anti-tumor responses, but also enabling widespread immune activation that can impact multiple organs. Understanding this balance is key to safer, more targeted cancer therapies.
In this regard, advances in immunotherapy continue to evolve toward more precise approaches. Intratumoral immunotherapy represents one of these innovative strategies, as it seeks to administer treatment directly into the tumor, concentrating its effect at the site of disease. This approach allows for localized activation of the immune response, promoting the release of tumor antigens and the activation of immune cells within the tumor microenvironment, while reducing exposure to the rest of the body.
By limiting systemic activation, these approaches have the potential to reduce the frequency or intensity of certain autoimmune effects, contributing to a better balance between efficacy and safety. In other words, the goal is not only for the immune system to attack cancer, but to do so in a more targeted and controlled way.
Treatment decisions should be based on clinical guidelines and scientific evidence. Resources such as UpToDate and specialized texts like SITC’s Guide to Managing Immunotherapy Toxicity provide key guidance for managing these complications.
Immunotherapy represents a significant advancement in cancer treatment, with the potential to generate durable responses. Its effectiveness is closely linked to activation of the immune system, which implies a delicate balance between benefit and risk. Understanding these mechanisms allows for anticipation of adverse effects and their timely management.
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Reference: Jason R. Williams, 15 Oct 2019, The Immunotherapy Revolution: The Best New Hope For Saving Cancer Patients’ Lives, https://williamscancerinstitute.com/the-immunotherapy-revolution
