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How Cancer Convinces The Body’s Own Defenders To Betray It

Writer: PULSE MedTech
PULSE MedTech
Aug 26
6 min read

The immune system is supposed to destroy cancer. Yet some tumors manage to do something remarkable: instead of defeating the immune system by force, they recruit immune cells and use them to fight on their side. Among the most important recruits are macrophages, which are immune cells that normally engulf dangerous invaders and damaged tissue. Instead of attacking the cancer, however, these macrophages can become its allies, helping tumors grow and spread. 


UC San Diego's Dr. Judy Varner can provide some key insight into how this happens. Dr. Varner is a professor of pathology and medicine at UCSD, Director of Faculty Mentoring for the Department of Pathology, and co-leader of the Solid Tumor Therapeutics program in the Moores UCSD Cancer Center. With a background in research on cell adhesion molecules and migration as it relates to disease, she is currently in research involving tumor growth promoted by macrophages. More specifically, she helped discover that PI3K-γ (phosphoinositide 3-kinase gamma) acts as a molecular signal that directs immune cells to support tumor growth. By identifying PI3K-γ's role in helping tumors evade the immune system, researchers uncovered a new strategy for making cancer treatments more effective.


This raises an important question: how can cells meant to protect us end up helping a tumor instead? To answer that, we first need to understand the typical role of the immune system. Simply put, the role of the immune system is to protect the body from harmful “invaders” such as bacteria, viruses, parasites, and cancer cells. With a normally functioning immune system, the body is able to recognize cells that are foreign and may be harmful, respond by killing these cells, and create antibodies to kill future germs that may enter your body. There are many components of the immune system, such as white blood cells, cytokines, antibodies, lymph nodes, and the spleen.


One type of immune cell called a monocyte circulates throughout your bloodstream until damaged tissue signals to these molecules to enter the tissue. A large number of monocytes will enter the damaged tissue and become macrophages. Typically, macrophages will engulf and destroy harmful cells, but in a tumor setting they can be reprogrammed to support tumor growth rather than inhibit it. 


A tumor is far more than an isolated collection of cells, in fact, the cells surrounding it are incredibly important as well. The tumor microenvironment (TME) describes the cells, tissues, and blood vessels that surround a tumor. In the TME, cells that normally protect the body from harmful invaders are exposed to signals from the tumor that cause the cells to protect the tumor and suppress the immune response, as seen with tumor-associated macrophages (TAMs). In this way, TAMs work as double agents which originate from the immune system, but switch sides when exposed to tumor signals. 


Understanding how tumors reprogram macrophages requires looking at the molecular signals that control cell behavior. One important class of signaling molecules is known as kinases. Kinases are a type of protein which put a phosphate group onto other molecules through a process called phosphorylation. This is important because that additional phosphate group can change the way that molecule interacts with its surroundings and other molecules. PI3Kγ is specifically a lipid kinase, which means it phosphorylates molecules that are part of the cell membrane. 


This is where Dr. Varner’s research comes into play. PI3Kγ creates a signalling complex on the cell membrane which can amplify signals from outside the cell that result in changes in gene expression and cell behavior. At first, Dr. Varner's team discovered that PI3Kγ helped monocytes enter tumors. Then, the story became even more interesting.


"We discovered this molecule was responsible for all this entry of monocytes into tumors," she explained. "Then we discovered that it did more than that. It controlled...the gene expression of those macrophages."


The team then went on to study what would happen if they inhibited the molecule or deleted the gene which codes for PI3Kγ. By taking PI3Kγ out of the picture, they found that they “could completely reverse this inhibitory behavior and… cause tumor shrinkage.” Without PI3Kγ transmitting the tumor's signals, macrophages stopped acting like accomplices. Instead of protecting the cancer, they regained many of their normal immune functions, and the tumors began to shrink.


With this discovery, scientists can now focus on developing new drugs that work to selectively inhibit this molecule. One common difficulty with developing medication, however, is that the molecule they are targeting may have a variety of functions, so targeting one function can have unwanted adverse effects. Fortunately, PI3Kγ is fairly specific to immune cells and is not highly expressed in other cell types, so this is not an issue. Additionally,  PI3Kγ does not have a dose-limiting toxicity. Therefore, even when tested at high doses, the drug does not have toxic or life-threatening effects on the patient. This does not mean that the medication is without side effects, but they are limited to temporary rash, fever, and a higher likelihood of skin infection.  


Dr. Varner contributed to the development of a drug which targeted PI3Kγ and proved successful in phase 1 clinical trials of 350 patients with solid tumors. However, the pharmaceutical company has since been unable to fund further development. In light of this, Dr. Varner is preparing to start a company that will develop a new and better drug to inhibit PI3Kγ as a part of the treatment regimen for patients with solid tumor cancers.


While these treatments show great promise for cancer patients, the most effective treatment for patients appears to be a combination of treatments.


Currently, many cancer treatment plans involve both chemotherapy and immune therapy. Chemotherapy targets and kills rapidly dividing cells such as cancer cells, while immune therapy helps the immune system better recognize and kill tumor cells. Unfortunately, macrophages can reduce the effectiveness of immunotherapy by inactivating modified T cells, which are immune cells that have been genetically engineered to recognize and kill cancer cells. So, a drug which inhibits PI3Kγ would in turn limit the presence of macrophages and potentially improve patient outcomes.


Dr. Varner remains optimistic that PI3Kγ inhibitors can help provide a variety of patients with better, more effective treatment. 


“We have high hopes that this will be useful in treating patients with any kind of cancer.”


Further evidence in support of adding PI3Kγ inhibitors to cancer treatment regimens is demonstrated by exceptional responders to glioblastoma treatment. Glioblastoma is an aggressive form of brain cancer and most patients have a life expectancy of 12-18 months after diagnosis, even with treatment. A person who survives more than two years past treatment is considered an exceptional responder, and these patients consistently had lower levels of microglia and macrophages at tumor sites than their counterparts, which is something that would be controlled by PI3Kγ.


Cancer has spent thousands of years learning how to manipulate the body’s own defenses by conniving some of the immune system’s strongest defenders to fight for the wrong side. However, Dr. Varner’s research suggests that this betrayal may be reversible. As researchers continue developing PI3Kγ inhibitors, the goal is not simply to attack tumors directly, but to help the immune system remember whose side it has been on all along.  †


Written by Staff Writer Audrey Gayou (agayou@ucsd.edu) 



References

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Immunotherapy vs. Chemotherapy: What’s the Difference?, www.cancercenter.com/community/blog/2025/09/immunotherapy-vs-chemotherapy. Accessed May 2026.

Lanahan, Stephen M, et al. “The Role of Pi3kγ in the Immune System: New Insights and Translational Implications.” Nature Reviews. Immunology, U.S. National Library of Medicine, Nov. 2022, pmc.ncbi.nlm.nih.gov/articles/PMC9922156/.

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PI3Kγ Inhibition Suppresses Microglia/TAM Accumulation in Glioblastoma Microenvironment to Promote Exceptional Temozolomide Response | PNAS, www.pnas.org/doi/10.1073/pnas.2009290118. Accessed Apr. 2026.

professional, Cleveland Clinic medical. “Your Immune System: What You Need to Know.” Cleveland Clinic, 22 Dec. 2025, my.clevelandclinic.org/health/body/21196-immune-system.

Rob MacDonald, PhD. “Immunophenotyping: Myeloid Cell Markers & Identification.” Immunophenotyping: Myeloid Cell Markers & Identification, Cell Signaling Technology, 20 May 2026, blog.cellsignal.com/immunology-what-cells-have-a-myeloid-lineage-and-how-are-they-identified.

Scarborough, David. “SciMed Biotech Podcast with Judith Varner.” SciMed, SciMed, 18 Oct. 2023, scimed.io/news/judith-varner-scimed-biotech-podcast.

 
 
 

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