Immune checkpoint inhibitors, such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 therapies, demonstrated that under the right conditions, the immune system can generate powerful and, in some cases, durable anti-tumor responses. However, alongside these remarkable successes, a more concerning observation emerged: in a subgroup of patients, tumors not only resisted treatment, but appeared to grow dramatically faster after the initiation of immunotherapy.
This phenomenon became known as hyperprogression.
Instead of stabilizing the disease or slowing tumor growth, some patients experienced an abrupt acceleration of tumor burden, clinical deterioration, and reduced survival shortly after starting treatment. The idea initially generated controversy. Some researchers believed these were simply naturally aggressive tumors that were already destined to progress rapidly. Others began considering that there could be a true biological response associated with immunotherapy itself. Over time, accumulating clinical evidence suggested that hyperprogression is probably a real phenomenon, although its exact mechanisms are still not completely understood.
The Immune System Does Not Always Act Against Cancer
One of the most important ideas in modern immunology is that the immune system has dual functions. Some immune cells attack danger and help eliminate it, while others exist to control inflammation and prevent excessive damage to healthy tissues. Cancer learns how to exploit this balance.
Cancer is not simply a disorganized mass of cells growing uncontrollably. It is now understood more as a complex and adaptable biological ecosystem capable of modifying its environment to favor its own survival. Tumors can recruit regulatory immune cells, suppressive macrophages, and inhibitory molecules that reduce the ability of the immune system to recognize and destroy malignant cells.
This concept is fundamental to understanding hyperprogression.
Figure 1. Overview of pseudoprogression and hyperprogression following immunotherapy, highlighting potential contributions from immune regulation, tumor microenvironment remodeling, and molecular alterations.
Checkpoint inhibitors work by removing certain immune “brakes.” In many patients, this allows cytotoxic T cells to reactivate and recognize the tumor. However, the immune system is extraordinarily complex. If the tumor microenvironment continues to be dominated by immunosuppressive signals, removing a single brake may not be enough to generate an effective response. In some contexts, immune activation could even stimulate inflammatory processes that the tumor itself eventually exploits to its advantage.
What Exactly Is Hyperprogression?
Hyperprogression refers to a rapid acceleration of tumor growth after starting immunotherapy. In practical terms, it means that the cancer appears to advance much faster than expected once treatment begins.
Clinically, this may manifest as:
- accelerated increase in tumor size,
- appearance of multiple new lesions,
- rapid worsening of symptoms,
- and significant deterioration of the patient’s general condition.
One of the challenges is that there is still no universal definition. Some studies compare tumor growth rates before and after initiating immunotherapy, while others use radiological criteria combined with clinical deterioration.
In addition, hyperprogression must be differentiated from another phenomenon known as pseudoprogression. In pseudoprogression, the tumor initially appears to grow on imaging due to immune-cell infiltration and local inflammation, but may later decrease in size. Distinguishing between both scenarios can be extremely difficult, especially during the first weeks of treatment.
And this is where one of the greatest dilemmas of modern immuno-oncology emerges: should treatment continue while waiting for a delayed response, or should it be stopped because the tumor is truly accelerating?
Why Could Hyperprogression Occur?
The exact biology behind hyperprogression is still under investigation, but several important hypotheses attempt to explain why it occurs.
One of the central ideas is based on regulatory immune cells. Among the most studied are:
- tumor-associated macrophages (TAMs),
- regulatory T cells (Tregs),
- and myeloid-derived suppressor cells (MDSCs).
These populations can reduce cytotoxic T-cell activity and generate an environment more favorable for tumor survival. In some contexts, checkpoint inhibition could alter the immune balance in such a way that these immunosuppressive signals end up predominating rather than decreasing.
This may occur because immunotherapy seeks to release certain immune “brakes” to allow T cells to attack the tumor more intensely. However, if the tumor microenvironment is already deeply dominated by suppressive signals, chronic inflammation, or dysfunctional immune cells, simply removing those brakes may fail to properly direct the immune response and instead generate a disorganized response that the immune system attempts to compensate for with regulatory signals, causing, in some patients, the activation of biological processes that ultimately help the tumor.
Another important hypothesis involves inflammatory cytokines, signaling molecules that coordinate inflammation, tissue repair, and vascular remodeling when the immune system becomes intensely activated, but which the tumor uses to its advantage through these same processes to repair itself and spread.
Genomic alterations associated with increased risk of hyperprogression have also been identified, including amplifications in genes such as MDM2/MDM4 and alterations in EGFR. These alterations could modify how tumor cells respond to immune and inflammatory signals. However, there is currently no definitive biomarker capable of predicting with certainty which patients will develop hyperprogression.
Reality is probably multifactorial. Rather than originating from a single molecular pathway, hyperprogression appears to arise from a complex interaction between tumor biology, immune composition, inflammation, metabolism, and specific characteristics of the tumor microenvironment.
Beyond Simply Activating the Immune System
One of the messages most frequently emphasized by Dr. Jason Williams is that the success of immunotherapy does not depend solely on “activating” the immune system. An effective anti-tumor response requires coordination among multiple biological processes.
Many tumors are considered immunologically “cold.” This means they have little T-cell infiltration or limited ability to be recognized by the immune system. In those cases, removing inhibitory checkpoints may not be sufficient.
For this reason, there is growing interest in combination therapies designed to:
- increase the release of tumor antigens,
- improve antigen presentation,
- recruit immune cells,
- reduce immunosuppressive signals,
- and remodel the tumor microenvironment.
At Williams Cancer Institute, one of the most discussed strategies is the combination of intratumoral immunotherapy with ablation therapies, such as cryoablation or pulsed electric field (PEF) ablation. These techniques seek to locally destroy the tumor while releasing tumor antigens capable of stimulating immune recognition.
The concept is frequently described as a type of “in situ vaccine”: the patient’s own tumor becomes the source of information that trains the immune system.
The Importance of Proper Patient Selection
The challenge is that responses to immunotherapy are profoundly individual. Two patients with the same type of cancer may respond in completely different ways depending on genetics, microbiome composition, immune status, previous treatments, and characteristics of the tumor microenvironment.
This has driven the idea that the future of immunotherapy will probably depend on increasingly personalized strategies.
The Microbiome Could Also Influence
In recent years, the gut microbiome has become one of the most fascinating areas of immuno-oncology.
Numerous studies show that certain intestinal bacteria can influence the immune response and modify the effectiveness of immunotherapy. Some species appear to favor immune activation, while others may promote more suppressive environments.
Although much research is still needed, there is a possibility that microbiome alterations also contribute to disorganized or maladaptive immune responses associated with hyperprogression.
A Reminder of Cancer’s Complexity
Hyperprogression is an important reminder that immunotherapy does not function as a simple immune “on switch.” The immune system is one of the most complex biological systems in the human body, and therapeutically modifying it requires precision.
Some patients experience deep and durable responses. Others obtain limited benefits. And a small subgroup may even deteriorate rapidly after treatment.
Understanding why these differences occur has become one of the greatest challenges in modern oncology.
Main 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
