Misfolded proteins might be one reason why immunotherapy fails

Hello Nature readers,
This week, we discover a possible mechanism behind immunotherapy failure, learn that ‘armoured’ CAR T cells can penetrate solid tumours and investigate how oncologists are responding to drug shortages.

What causes immunotherapy to fail?

A build-up of toxic, misfolded proteins causes immune cells to become exhausted and might make cancer immunotherapy less effective. Researchers examined the proteins inside exhausted T cells taken from mice with colon and bladder tumours. Instead of slowing protein synthesis in response to stress, these T cells ramped up the production of misfolded proteins, creating a ‘proteotoxic stress response’ that overwhelmed the cell. This pathway could be targeted as a way to prevent T-cell exhaustion and boost cancer immunotherapies, the authors conclude.

‘Armoured’ CAR Ts attack solid tumours

CAR T cells often can’t penetrate solid tumours. But attempts to embolden them by adding immune-boosting molecules to the mix have failed because this cocktail can be toxic if not targeted directly at the tumour. Researchers have solved this problem by creating ‘armoured’ CAR T cells that carry a fusion of PD-L1 and IL-12 proteins into the tumour. Greater antitumour activity was seen in mice with prostate and ovarian cancers given these boosted CAR T cells compared with controls. “We believe our αPD-L1–IL-12 engineering strategy presents an opportunity to improve CAR-T cell clinical efficacy and safety across multiple solid tumour types,” write the researchers.

How oncologists respond to drug shortages

US oncologists appeared to follow expert guidance when it came to responding to shortages of the cancer drugs cisplatin and carboplatin in 2023. This was “an encouraging sign, given historically slow integration of guidelines into clinical practice”, writes health-services researcher John Lin and his co-authors. After drug shortages were announced, the American Society of Clinical Oncology provided guidance on how to prioritize use of cisplatin and carboplatin for the people who needed it most — and prescribing data appeared to reflect this advice. “National organizations should prepare for future drug shortages by developing systems for real-time responses,” the authors conclude.

Restore order, calm cancer

Chemotherapy often makes it harder for cancer cells to replicate by unleashing genetic chaos. In a counterintuitive move, researchers have reduced the spread of an aggressive form of breast cancer in mice by doing the opposite. They restored order to cancer cell division by blocking a protein called EZH2, which would otherwise cause triple-negative breast cancer cells to divide abnormally, allowing cells to travel to distant organs.

Drug resistance tracked cell by cell

The evolution of drug resistance in ovarian cancer has been tracked in real time by sequencing tumor cells removed during surgery and then monitoring changes in circulating tumour DNA. The technique, called CloneSeq-SV, was used to examine changes across 18 people with high-grade serous ovarian cancer over more than five years. “Using this new method, we could see that the cells that are resistant were present at the time of diagnosis, and that they were able to multiply as cells that were more sensitive to treatment died off,” computational oncologist and study co-author Sohrab Shah said in a statement.

Ageing and cancer: a feedback loop

Around 90% of cancers occur in people over 50, and cancer and its treatments can also drive ageing, creating a feedback loop that exacerbates frailty and contributes to other age-related diseases. As the world’s population ages, the healthcare and economic burdens related to cancer will be “far from trivial”, argues a Nature Reviews Cancer editorial. “Studying cancer within the context of ageing is therefore essential,” says the editorial, which is linked to a focus issue on the subject.