Chemotherapy can be life-saving for many patients, but not all tumours respond—and some that do, may eventually become resistant.

Investigators at Houston Methodist have identified a possible explanation for this resistance, offering new insight into why certain cancers evade treatment.

The study, published in Nature Communications found that, in some cases, chemotherapy may unintentionally reshape the immune system in ways that allow cancer to persist, even as it kills tumour cells.

Led by Keith Chan, Ph.D., Neal Cancer Centre Distinguished Chair at Houston Methodist, the study found that gemcitabine, a standard chemotherapy, triggers a type of cancer cell death called pyroptosis—which causes cells to burst open and release inflammatory signals that inhibit tumour treatment.

The research, “Chemotherapy-induced activation of caspase-1 and IL-1α release by cancer cells remotely skews myelopoiesis to drive pro tumorigenic systemic neutrophil-dominant inflammation,” appears in Nature Communications.

Instead of activating the immune system to attack the tumour, this process causes cancer cells to release IL‑1α—a molecule that travels through the bloodstream to the bone marrow, disrupting and skewing how new immune cells are produced.

Specifically, this molecule causes the bone marrow to shift from producing beneficial immune cells that target cancer to producing different cells that support tumour growth, ultimately leading to poor patient outcomes.

“We noticed that IL‑1α released by the dying cancer cells travels to the bone marrow and reprograms the immune system negatively,” Chan said.

“However, as shown in the results, by blocking the trigger for the inflammatory signal or neutralising the disruptive molecule, we were able to stop this harmful chain reaction and restore normal bone marrow activity and help the immune system work with chemotherapy instead of against it.” 

For the next steps, Dr. Chan said the researchers will work toward moving into an early-phase clinical trial, laying the groundwork for evaluating safety, feasibility and early signs of effectiveness in patients.

The project was initiated by Kazukuni Hayashi and Fotis Nikolos, with Stephen Wong and Ethan Subel as key co-contributors.

Other collaborators on the study include Wisnton Huang, Yung Huang, Hongbo Gao, Haly Garcia, Sophie Porter, Mustafa Karabicici, Michael Brooks, Zheng Yin, Renil Titus, Yulin Li, Lan Zhou, Ziad El-Zaatari, Stephen Wong, Dharam Kaushik and Raj Satkunasivam from Houston Methodist; Efrosini Tsouko, Crystal Shin and Lisa Hayes from Baylor College of Medicine and Dimitrios Korentzelos from the University of Pittsburgh Medical Centre.

The study was funded in part by grants from the National Institute of Health, the U.S. Department of Defence and Cancer Prevention and Research Institute of Texas.

Source: Houston Methodist