2021 in Review

In our Focus on 2021 in Review, the Nature Cancer team and leading experts look back at the biggest developments for the cancer field over the past 12 months.

From a first-in-class KRAS approval to the latest agonist antibody failures, 2021 was another busy year for cancer drug developers.

Despite widespread vaccination, patients with cancer still face a slew of pandemic-related challenges.

Elisabete Weiderpass is an expert in cancer epidemiology and cancer prevention. She has been the Director of the International Agency for Research on Cancer, the specialized cancer agency of the World Health Organization, since January 2019. She spoke with Nature Cancer about 2021 and the years ahead.

50 years after the National Cancer Act was signed into law, Nature Cancer spoke with the National Cancer Institute Director Dr Ned Sharpless about the progress in cancer research and care, the complications of the pandemic and what to expect in the future.

Combination of approved immune checkpoint inhibitors has shown remarkable efficacy in the treatment of melanoma, but at the cost of high toxicity. After years of intensive research, inhibitors of the immune checkpoint molecule LAG-3 are now demonstrating promising results and favorable toxicity profiles in clinical trials in combination with inhibition of the checkpoint molecule PD-1.

The rapid progression of KRAS(G12C) inhibitors from preclinical characterization to the clinic has radically changed the perception of the KRAS oncogene as an undruggable target. Here we discuss ongoing and future possibilities for developing therapies using these inhibitors in clinical settings.

The COVID-19 pandemic has impacted cancer care globally, the consequences of which are still not well understood. Through the lens of the impact in India, we emphasize the importance of continuing cancer care even during extenuating public health circumstances, and of strengthening health systems as a global priority.

Rapid progress in the molecular characterization of cancer genomes has been enabled by technology and computational analysis, and large databases now exist. Novel cancer therapeutics have resulted that more precisely target the vulnerabilities revealed by genomic analysis. Emergent efforts that link the two, using machine learning approaches and circulating DNA from cancer cells, are furthering cancer diagnosis and precision medicine.

Recent advances in single-cell multiomics have provided holistic views of the multifaceted state of a cell and its interaction with the environment. The rapid development of these technologies has offered a unique opportunity to analyse the molecular and cellular heterogeneity in cancer, and could lead to better cancer diagnosis, treatment and prognosis.

Cancer multi-omics data has greatly expanded over recent decades, surpassing the human ability to extract meaningful information. The successful implementation of artificial intelligence systems into clinical pipelines to interpret complex datasets, and improve the outcomes of patients with cancer, demands strong validation using real-world evidence while also being mindful of ethical and social aspects.

Despite the profound clinical success of immune-checkpoint inhibitors, their effectiveness is limited by intrinsic and acquired resistance. Bullman, Zitvogel and colleagues provide their views on two clinical trials modulating the microbiome of immunotherapy-resistant patients with melanoma via transplantation of fecal microbiota from patients who responded to immunotherapy.

Twelve early-career investigators share their thoughts on the challenges faced by their teams and communities during the past year, and look ahead to new opportunities for 2022.

Garofano et al. use single-cell RNA-sequencing data to classify glioblastomas along a metabolic axis of mitochondrial and glycolytic/plurimetabolic states and a neurodevelopmental axis of proliferative/progenitor and neuronal states.

Ma et al. apply few-shot learning to train a neural network model on cell-line drug-response data, and they subsequently transfer it to distinct biological contexts including different tissues and patient-derived tumor cells and xenografts.

Walsh and colleagues use prospective sequencing in a large cohort of pediatric patients with solid tumors to detect mutations in cancer predisposition genes and guide downstream clinical care.

Ferraro et al. report that fatty acid synthesis is needed for brain cancer metastasis and show that blocking this process by inhibiting fatty acid synthase reduces the metastatic growth of breast cancer cells in the brain.

Quail and colleagues demonstrate that neutrophil-derived ROS and extracellular traps (NETs) mediate breast cancer metastasis to the lungs by altering endothelial junctional adhesions, thus favoring vascular permeability and transendothelial migration of cancer cells.

D’Andrea and colleagues identify the antibiotic novobiocin as a specific POLQ inhibitor with preclinical activity in homologous-recombination-deficient breast and ovarian tumors in vivo, including these with acquired PARP inhibitor resistance.

Obenauf and colleagues report that acquired resistance to BRAF and MEK inhibitors in melanoma confers cross-resistance to immune checkpoint blockade by fostering a cancer cell–instructed, immune-evasive tumor microenvironment.

Italiano and colleagues demonstrate the utility of mature tertiary lymphoid structures to predict response to immunotherapy, with pathologic analysis in three independent patient cohorts spanning multiple tumor types.

Yarchoan and colleagues present a single-arm phase 1 clinical trial of cabozantinib with immune checkpoint inhibition for patients with hepatocellular carcinoma. Using high-dimensional spatial analysis, they identify immune features enriched in responders.

Pappalardi and colleagues identify a potent noncovalent DNMT1-selective inhibitor with improved tolerability and efficacy in preclinical AML models compared with clinically validated covalent pan-DNMT inhibitors.

Lehtiö and colleagues perform proteogenomic analysis of non-small cell lung cancer and identify molecular subtypes with distinct immune-evasion mechanisms and therapeutic targets and validate their classification method in separate clinical cohorts.

Turajlic and colleagues assess longitudinal antibody and cellular immune responses against SARS-CoV-2 variants of concern in patients with cancer, following either recovery from SARS-CoV-2 infection or vaccination, in two back-to-back reports from the CAPTURE study.