Uneven Drug Distribution in Tumors: A New Understanding of Cancer Treatment Variability

Inside cancer cells, certain drugs may not behave as expected. Instead of spreading evenly, some develop into trapped in microscopic compartments that slowly release them over time. This discovery hints at a deeper layer of complexity in cancer therapy. Credit: Shutterstock

Why Cancer Treatments Vary in Effectiveness

A new study published in Nature Communications sheds light on why promising cancer treatments can produce dramatically different results across patients. One of the biggest challenges in cancer treatment is the variability in response – a therapy that works well for one patient may completely fail in another.

Mapping Drug Delivery with Advanced Imaging

Researchers at the MRC Laboratory of Medical Sciences (LMS), led by Dr. Louise Fets, examined how PARP inhibitors – a class of targeted drugs – spread through ovarian tumor samples. Using advanced imaging techniques, they found that these drugs can accumulate inside lysosomes, which are cellular structures that act as “recycling centers.” This buildup allows the drugs to be stored and released over time, influencing treatment effectiveness.

For a treatment to work, the drug must accumulate inside cancer cells at levels high enough to kill them. Scientists have not fully understood how drugs are distributed within tumors or what controls this process, until now.

How the Study Was Conducted

The researchers used thin slices of ovarian tumors taken from patients and kept them alive in the lab (“explants”). These samples were treated with PARP inhibitors, allowing scientists to directly observe how the drugs moved through real human tumor tissue. Mass spectrometry imaging was used to create detailed maps showing where drug molecules collected. This was combined with spatial transcriptomics to compare gene activity in areas with high and low drug concentrations within the same sample.

The findings revealed significant differences in drug levels across different regions of the same tumor and between patients, even when the same dose was used. “A novel aspect of this study was the use of mass spectrometry imaging to directly measure and visualise drug uptake in patient tumor tissue. Through the spatial mapping of drug molecules, we could pinpoint regions of high and low drug and compare gene expression, from the same tissue slice, using spatial transcriptomics,” says Dr. Zoe Hall, senior author and Associate Professor at Imperial’s Department of Metabolism, Digestion and Reproduction.

Lysosomes as Drug Reservoirs

The study found that lysosomes play a key role in this uneven distribution. Some PARP inhibitors are drawn into these compartments and stored there instead of spreading evenly throughout the cell. These reservoirs act as slow-release storage sites, holding the drug and releasing it gradually over time. This leads to higher exposure in some cells, while others receive much less of the drug.

Not all PARP inhibitors behave the same way. The study showed that drugs such as rucaparib and niraparib are affected by this process, while others like olaparib are not. “We were surprised to see large variability in drug accumulation at the single-cell level. This variability was driven by the build-up of a drug in lysosomes, which are acting as reservoirs, increasing the exposure of cancer cells to drugs, by storing and releasing the drug when needed,” says Dr. Carmen Ramirez Moncayo, first author and Postdoctoral Researcher at the LMS.

The Future of Personalized Cancer Treatment

PARP inhibitors are already used to treat ovarian, breast, and prostate cancers, and are being tested in clinical trials for many other types. A better understanding of how these drugs are stored and distributed inside cells could lead to more personalized treatment strategies that improve outcomes and reduce the risk of resistance or relapse.

“By understanding how drugs are taken up into cells, we can understand whether this influences why cancer drugs work for some people and not for others. Eventually, we hope to be able to study the molecular signature of a patient’s tumor to help tailor therapeutic approaches in a more personalized way,” says Dr. Louise Fets, senior author and Head of the LMS’ Drug Transport and Tumor Metabolism Group.

Future research will use animal models and larger patient studies to better understand how drug delivery, tumor structure, and lysosomal storage interact in real clinical settings, including in relapsed cancers.

Reference: Moncayo, C.R., Restuadi, R., Zhang, G. et al. Multimodal imaging reveals a lysosomal drug reservoir that drives heterogeneous distribution of PARP inhibitors. Nat Commun 15, 2338 (2024). https://doi.org/10.1038/s41467-026-70558-1

This research was supported by funding from the Medical Research Council, Cancer Research UK, a PhD studentship from the Integrative Toxicology Training Partnership administered by the MRC Toxicology Unit, and a Victoria’s Secret Global Fund for Women’s Cancers Career Development Award, in partnership with Pelotonia and AACR.