REHOVOT, ISRAEL — November 19, 2025 — Immunotherapy, which harnesses the body’s immune system to fight cancer, has reshaped modern oncology. Yet despite its success with several cancers, many patients still fail to respond to therapy or relapse. Scientists have long sought ways to pinpoint how cancer shuts down immune responses and to flip the switch back on at that site. A new study from the Weizmann Institute of Science, published today in Cell, suggests that the solution may lie within the tumor’s own defenses.
The study focuses on macrophages — large, versatile cells that perform essential functions throughout body tissues but, in the tumor microenvironment, often begin collaborating with cancer. “For years we have known that in cancer, macrophages can be both the problem and the solution,” says Prof. Ido Amit, director of Weizmann’s Immunotherapy Research Center. “Tumors hijack them to suppress immune responses and promote their own growth. Our goal has been to re-educate these cells rather than remove them.”
Earlier studies from Amit’s team and others identified a subgroup of macrophages-turned-tumor-allies that are particularly involved in suppressing immune activity. Their defining feature is the high expression of a receptor called TREM2, which coordinates their anti-immune activity. Patients whose tumors contain these macrophages tend not to respond well to treatment and have lower survival rates.
In the new study, a team led by Michelle von Locquenghien, Dr. Pascale Zwicky and Dr. Ken Xie of Amit’s lab designed biological molecules intended to guide these macrophages back on track: a new type of antibody that awakens a patient’s anti-tumor immunity by simultaneously blocking TREM2-expressing macrophages and prompting other immune cells to attack the cancer. The latter is achieved by exposing immune cells to an activating protein known as a cytokine. The researchers call this new class of immune-activating molecules MiTEs, short for myeloid-targeted immunocytokines and natural killer/T-cell enhancers.
A key challenge was avoiding severe side effects. When the immune system is activated too strongly across the body, it cannot always distinguish friend from foe and can damage healthy tissue. To limit this risk, the researchers used an engineering strategy that equips MiTEs with molecular masks that keep the IL-2 cytokine dormant while the molecules circulate. Only when MiTEs enter the tumor is the mask removed by enzymes found at the tumor site, activating the cytokine only where needed.
“The dual function of MiTEs enables them to attack the tumor from multiple immune angles at once,” von Locquenghien says. “These molecules are designed to turn both the tumor’s allies and its suppressive environment into its Achilles’ heel.”
Zwicky notes the promise of this approach, in part because it acts through immune pathways common to multiple cancers rather than through tumor-specific antigens. “Because MiTEs act through immune mechanisms present in many patients and cancer types, they have the potential to be broadly applicable,” she says.
This advance was made possible through technologies including spatial transcriptomics, which reveals where genes are active in a tissue. “We mapped the spatial immune architecture in human tumors at single-cell resolution and found that the TREM2-carrying macrophages were often positioned near immune killer cells that appeared exhausted,” Xie says. “That spatial insight led us to design biological molecules that could block immune-suppressing macrophages while delivering a localized activation signal to the killer cells, energizing them to attack the tumor while minimizing collateral damage.”
This approach reflects a wider trend in cancer immunology: designing therapies that reshape the tumor microenvironment rather than solely targeting cancer cells. “The future of immunotherapy lies in combining safety with precision — reprogramming the immune ecosystem from the inside rather than targeting cancer cells directly,” Amit says.
In mouse studies, MiTEs caused tumors to shrink and triggered immune remodeling in both macrophages and immune killer cells. When tested on renal cell carcinoma tissue samples from patients, MiTEs caused strong immune activation, including the awakening of killer immune cells. To advance MiTEs toward clinical use, the team plans to examine long-term safety and explore combinations with existing treatments. Early data suggest that MiTEs act synergistically with checkpoint inhibitors, amplifying the overall immune response.
The findings outline a potential blueprint for a new generation of safe, programmable immunotherapies capable of overcoming resistance across a broad range of cancers. “Our work demonstrates that by understanding the tumor’s own defense mechanisms, we can turn them into opportunities,” Amit says. “With MiTEs, we may have found a way to convert the tumor’s shield into the weapon that defeats it.”
Also participating in the study were Dr. Diego Adhemar Jaitin, Dr. Fadi Sheban, Dr. Chamutal Gur, Reut Sharet Eshed, Eyal David, Kfir Mazuz, Dr. Roberto Avellino and Dr. Assaf Weiner of Amit’s lab in Weizmann’s Systems Immunology Department; and Dr. Adam Yalin, Dr. Florian Uhlitz, Caroline Jennings Marin, Dr. Ankita Sankar and Devin Mediratta of Immunai, New York.
Prof. Ido Amit is the incumbent of the Eden and Steven Romick Professorial Chair. His research is supported by the Moross Integrated Cancer Center; the Elsie and Marvin Dekelboum Family Foundation; the Lotte and John Hecht Memorial Foundation; and Daniel Andreae.