Homing in on Solid Tumor Cancers with CAR-T Therapy
by Joanna Zhu
Franklin College of Arts and Sciences, Department of Biochemistry and Molecular Biology and Division of Biological Sciences
CAR-T therapy, solid tumor cancers, immunotherapy
What if we could design a cellular homing missile to specifically target and destroy cancer cells in our body? In truth, the body already possesses such capabilities in the form of T-cells. But as effective as these cells can sometimes be in hunting down and killing cancer cells, they first need to receive the message from other immune cells and signaling molecules to activate and subsequently target these malignant cells. It can take several days to even a week to reach a peak response, which in some cases is enough time for cancer to take over the body, such as in acute leukemias (Pennock et al., 2013; Wang, 2018). Even once our T-cells are activated, cancer has a knack for dodging immune responses, making them especially hard to target (Tufail et al., 2025).
To tackle this problem, scientists discovered a way to engineer T-cells to directly recognize cancer cells without relying on other immune cells or signaling molecules. This led to the development of the powerful immunotherapy known as chimeric antigen receptor T-cell (CAR-T) therapy. Like the formidable chimera in Greek mythology, the receptor of an engineered CAR-T cell is a fusion of parts: it contains an antigen-binding site, a transmembrane domain, and a cellular signaling site (Zugasti et al., 2025). The transmembrane domain anchors the receptor in the membrane of the cell. The antigen-binding site recognizes a specific molecule or marker, called an antigen, on the surface of cancer cells. Once this antigen is bound by the receptor, the cellular signaling site is activated, initiating the T-cell’s killing mechanism (Zugasti et al., 2025). Together, these two parts allow a CAR-T cell to directly recognize and kill cancer cells. Furthermore, CAR-T cells also confer a supportive function, helping our own immune cells do their job. Dr. Sarwish Rafiq, program leader for CAR-T research at Emory’s Winship Cancer Institute, explains that CAR-T cells can spark a starting reaction for immune response, as they engage the endogenous immune system — our body’s natural defense mechanisms (personal communication, October 24, 2025). In other words, CAR-T cells can also function as an alert system, pinpointing the threat and directing our own T-cells to cancer cells that previously evaded detection.
On paper, the mechanisms of CAR-T cells make them a seemingly ideal candidate to take on cancer. But different types of cancers, namely blood and solid tumor cancers, have distinct characteristics that directly affect the efficacy of CAR-T therapy. Furthermore, each individual patient’s characteristics, such as age and other health conditions, also affect CAR-T cell efficacy. Beyond the medical side, the affordability and accessibility pose major barriers for many patients who can benefit from this therapy. Together, these challenges illuminate both the present limitations of CAR‑T therapy and the key frontiers where future breakthroughs may occur.
Efficacy in blood cancers vs. solid tumors
CAR-T therapy has revolutionized treatment for certain blood cancers, such as B-cell acute lymphoblastic leukemia, multiple myeloma, and several B-cell lymphomas, vastly improving outcomes overall. There are currently seven approved CAR-T cell therapies for select blood cancers (National Cancer Institute, 2025), which have largely been successful. For example, the first ever approved CAR-T therapy, Kymriah, was administered to children and young adults with relapsed acute lymphoblastic leukemia. Kymriah completely eliminated the relapsed cancer in 81% of the patients, with many surviving without relapse in a three-year follow-up (Laetsch et al., 2022). Another study showed that treatment of advanced follicular lymphoma with CAR-T therapy (Yescarta) resulted in complete remission of cancer in almost 80% of adult patients, again with no sign of relapse in many patients three years later (Neelapu et al., 2023).
In contrast, the therapy’s expansion into the realm of solid tumor cancers has been much more difficult. These cancers are particularly adept at evading detection, presenting false signals, and inactivating and killing immune cells (Du et al., 2025). Solid tumor cancers also produce a prominent hostile tumor microenvironment to suppress immune response and promote tumor growth, and this often prevents CAR-T cells from even making contact with tumor cells. Furthermore, antigens on one particular cancer cell can look vastly different from another, even if they are of the same cancer type (Du et al., 2025). This makes developing CAR-T receptors more difficult since no universal antigen can be identified, and hence the cancer cannot be eliminated in one fell swoop. All these challenges limit CAR-T cells’ ability to do their job.
Identifying and selecting antigens to develop specific CAR-T therapies against solid tumors is not easy to begin with. Unlike some blood cancers, there are not many commonly shared antigens (i.e., varied distribution) among cells within a tumor and or among patients (Guzman et al., 2023). Those few shared antigens that are highly expressed on cancer cells are called tumor-associated antigens. Even when these antigens are present, they are sparse, and the cell tends to decrease their expression (i.e., decrease production and presentation on the cell surface), making CAR-T therapy less effective against cancer cells (Majzner and Mackall, 2018). Furthermore, there is the risk of on-target/off-tumor toxicities, as some tumor-associated antigens are also present on normal cells of some tissues. This connection means that CAR-T cells could attack healthy tissue in addition to the cancer, potentially spelling out danger for the patient (Flugel et al., 2022).
However, despite these challenges, there has indeed been progress in developing CAR-T therapies against some solid tumors. Dr. Zhaohua Hou, a senior research scientist at Memorial Sloan Kettering Cancer Center, is one of many who hold hope for the therapy’s future. “I want you to know that this is just the beginning. The promise of immunotherapy began 30-40 years ago when the first engineered T-cells were produced. But CAR-T’s breakthrough really only came about 15 years ago,” he says, referring to the first clinical trials of CAR-T therapy resulting in complete remissions for leukemia patients (personal communication, October 10, 2025). Now, there are clinical trials for many solid tumor cancers such as gliomas, lung cancer, hepatocellular carcinoma, gastric cancer, prostate cancer, and ovarian cancer. In particular, CAR-T therapy has had noteworthy success in liver and gastric cancer so far, and it is rapidly advancing for certain types of brain tumors as well (Du et al., 2025).
Strategies to increase efficacy
To boost the efficacy of CAR-T therapy in solid tumor cancers, scientists are exploring various strategies such as combination immunotherapy, synthetic engineering, and genetic engineering. Besides obstacles stemming from the cancer itself, CAR-T cells face inherent challenges as well. T-cell exhaustion, marked by decreased function and proliferation, can occur from persistent stimulation from antigens, an immunosuppressive environment, and an altered metabolic state, among other factors (Wu et al., 2026). This is why, as Dr. Hou explains, “They need helpers to fight and win the battle” (personal communication, October 10, 2025). Just as CAR-T cells aid other immune cells to do their job, they will need the aid of their own to kill solid tumor cancer cells.
One strategy to increase CAR-T cell efficacy involves genetically engineering CAR-T cells to co-express, or produce simultaneously, small proteins called cytokines that are crucial for immune signaling and response to defend the body. These unique cells are referred to as “cytokine-armored” CAR-T cells, reflecting their supportive function. Two promising cytokines for this approach are IL-12 and IL-15. IL-12 armored CAR-T cells have been shown to be able to survive in the tumor microenvironment, maintain their killing function, and resist cell death (Yeku et al., 2017). More recently, a clinical trial of IL-15 armored CAR-T cells administered to patients with liver tumors demonstrated a 33% objective response rate. This result means that 33% of patients had either a significant decrease in tumor size or all signs of cancer disappeared completely. In patients treated with unarmored CAR-T cells, the objective response rate was zero percent (Steffin et al., 2024), demonstrating that without the help of cytokines, CAR-T cells would not be able to have such a large effect at all. It is no wonder that Dr. David Steffin, a pediatric oncologist at Texas Children’s Hospital and author of the study, asserted, “It is clear that cytokine co-expression makes a difference in the efficacy of CAR-T cells.” Going into more detail, he also notes that, “We know that two cytokines are better than one, and one is better than none. The combination of cytokines is also important” (personal communication, October 13, 2025). In this case, cytokines act like a shield, protecting CAR-T cells so that they can stay on course longer and impact their target with full potency.
Another combination strategy to increase CAR-T efficacy in solid tumor cancers involves chemotherapy and radiotherapy. Both can decrease the immunosuppressive microenvironment and kill tumor cells, releasing tumor antigens and stimulating an immune response. This can act as a helpful bridge for CAR-T therapy, Dr. Hou mentions (personal communication, October 10, 2025). These released antigens can also be useful for immunotherapy. But despite the possible synergistic effect with CAR-T therapy, the dosage and timing of chemotherapy and radiotherapy are very important. If this is not carefully managed, the viability and killing function of CAR-T cells may be affected (Wang et al., 2023).
As mentioned before, CAR-T cells themselves may also pose a risk to the patient due to on-target/off-tumor toxicities. The good news is that there are many adaptive strategies to control CAR-T cells. For more specific control of CAR-T cells, much research has gone into generating CAR-T cells with synthetic receptors that can activate or inactivate themselves when bound to specific molecules. This essentially serves as a cell communication tool and “safety switch” that can minimize on-target/off-tumor toxicity effects (Piraner et al., 2024). The safety switch mechanism is quite useful in case things go awry, especially in the clinical setting. A major side effect of CAR-T therapy is cytokine release syndrome (CRS), which can result in death if the patient does not overcome it (Cleveland Clinic, 2022). Essentially, CRS is hyperinflammation resulting from a large cytokine release from both tumor and CAR-T cells (Tvedt et al., 2021). It presents with flu-like symptoms: fever, fatigue, headache, low blood pressure, and so on. (Cleveland Clinic, 2022). Luckily, there are ways to manage CRS. Dr. Steffin explains that “We have a number of anti-inflammatory drugs that can be used- some don’t affect CAR-T cells, and some can knock them out, like steroids.” Likewise, synthetic receptors can also act as a brake on CAR-T cells in order to help manage CRS.
Culprits besides the cancer
CAR-T cells are often referred to as a “living drug” because the T-cells are isolated from patients themselves, genetically engineered, and then infused back into the patient, where they can continue multiplying and destroying cancer cells (Cleveland Clinic, 2022). Essentially, this process upgrades a population of the body’s T-cells to strike cancer. But the extent of the upgrade can depend on age and fitness of the individual, as Dr. Rafiq adds, “Each patient has their own characteristic T-cells,” (personal communication, October 24, 2025). Using aging as an example, she explains that the starting material changes over time, saying “For people with an elevated BMI, we also see worse durability of CAR-T cells” (personal communication, October 24, 2025). Beyond that, CAR-T therapy has no impact on some cancers at all, simply due to their inherent mechanisms. Dr. Rafiq points to acute myeloma leukemia as an example. Since myeloid cells themselves inherently suppress CAR-T cells, CAR-T is not very effective for this type of cancer (personal communication, October 24, 2025). To sum up, there are some external factors that may also contribute to the decreased efficacy of CAR-T therapy in solid tumor cancers.
Can we afford it?
In addition to the research, access to healthcare and cost are just as important. Despite major scientific advances, these barriers remain: “Even for FDA-approved CAR-T therapies, it’s hard to get access,” says Dr. Rafiq, “You’d have to go to a doctor who will write you a prescription for that and a place that has the resources to administer and monitor it” (personal communication, October 24, 2025). Generally, that would be at a cancer center near or in a city, meaning that if you live in a rural area, CAR-T therapy is largely inaccessible. The cost is also quite high, with a single infusion costing as much as $424,000 (Yescarta) to $543,828 (Kymriah), excluding extra procedures and facility costs (Cliff et al., 2023). The total cost of care could be over $1 million and up to $2 million (Borgert, 2021). A large part of the cost is due to production itself, but another is also the logistics, says Dr. Rafiq (personal communication, October 24, 2025). Extra care must be taken to not mix up patients’ T-cell infusions, and they must be stored at the right conditions and handled properly. These circumstances highlight the fact that even as groundbreaking science happens, we should be thinking about how to get that to the people who need it, in terms of both accessibility and cost.
Overall, CAR-T therapy is an exciting immunotherapy that has made strides in its application to some solid tumor cancers. Some challenges still stand in the way of it being fully effective, but many approaches are being researched to circumvent and deal with them. Patients, physicians, and researchers alike express optimism for the potential of CAR-T therapy in solid tumors. This shared sense of hope continues to drive the field forward. As Dr. Hou notes, “This may not be a problem that can be solved in 10, 20, 30, 50 years. But for any effective treatment, I think we should take the immune system into consideration. That’s why I have more hope and stronger confidence for immunotherapy compared to other treatments to address solid tumor cancers.” Indeed, science builds on itself slowly, and whether or not CAR-T becomes the future of cancer treatment remains to be seen. But for now, the best thing that we can do is place our trust in its potential.
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Acknowledgments: I’d like to thank Dr. Sarwish Rafiq, Dr. Zhaohua Hou, and Dr. David Steffin for allowing me to interview them and include their words of expertise in my article. Also, thank you to Dr. Gallagher for reading and giving me extensive feedback on my work!
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