Reviews & Analysis

Pharmacogenomic drug screening provides a promising platform for the discovery of anti-cancer drugs, in combination with biomarkers and mechanisms that confer therapeutic response. A study now pinpoints the mechanisms of sensitivity to dasatinib in T-ALL leukemia, identifying a T cell–differentiation switch that determines sensitivity to distinct drug modalities.

Shedding light on the mechanisms that underlie a durable response to immunotherapy, a recent study evaluating long-term survivors of melanoma treated with immunotherapy finds that tumor-associated T cell clonotypes are sustained over years and persist as expanded, cytokine IFN-γ–expressing resident memory T cells in the skin, with effector memory counterparts in the blood.

Kang and colleagues review recent advances and challenges in developing therapies for metastatic cancer and the clinical implications of ongoing and completed studies for metastatic disease.

Mukhopadhyay, Vander Heiden and McCormick review the metabolic landscape of RAS-driven cancers, the effects of RAS-directed metabolic reprogramming and opportunities for targeting these cancers therapeutically.

The complexity of glioblastoma is becoming increasingly recognized. Three recent studies used single-cell approaches that integrate cellular states, transcriptional trajectories, and metabolic alterations to uncover multiple dimensions of cellular and molecular heterogeneity and provide a framework for additional functional investigation and therapeutic development.

Metabolic reprogramming mediates resistance to therapy and rewires cancer-cell-signaling networks, paving the way to the discovery of enhanced treatment strategies through acquired vulnerabilities. A study now points to lipotoxicity dependent on Raf-1 kinase that occurs after activation of the liver receptor LXRα as a therapeutic intervention for the treatment of hepatocellular carcinoma.

The diversity of tumor cell responses to cyclin-dependent kinase 4/6 (CDK4/6) inhibition in breast cancer is a question not yet fully addressed. A recent study defines the effects of CDK4/6 inhibition on chromatin organization and shows that remodeling of the cancer cell epigenome mediates some of the key biological effects of these targeted therapy agents.

Chronic pancreatitis is a risk factor for pancreatic cancer; however, the mechanisms underlying cellular susceptibility to oncogenic transformation are complex. A recent study reports a damage-associated progenitor cell state, controlled by the transcription factors KLF5 and members of the AP-1 family, that initiates tumorigenesis in mouse models of pancreatic cancer in which the proto-oncogene KRAS is altered.

Achieving depletion of regulatory T cells while sparing tumor-specific effector T cells has long remained an elusive goal of immunotherapy. A new study describing the development of an antibody to the cytokine receptor CD25 optimized to ensure depletion of regulatory T cells without blocking binding of the cytokine IL-2 will reinvigorate interest in this therapeutic avenue.

The response to immunotherapy has been linked to human leukocyte antigen (HLA) genotype in certain cancers. A new study examining the interaction between cancer type–specific mutational exposures and the B44 and B27 HLA supertypes finds that patients with mutant peptides complementary to these supertypes receive the most benefit from immune-checkpoint blockade.

Immunostimulatory agents such as Toll-like receptor (TLR) agonists have shown promising antitumor efficacy but are associated with therapy-related toxicities when delivered systemically. Immune-stimulating antibody conjugates are now shown to deliver TLR agonists with potent preclinical antitumor activities.

Edelman Saul and colleagues review the challenges and strategies for implementing low-dose computed tomography screening for lung cancer in low- and middle-income countries.

Invariant natural killer T cells (iNKT cells) are innate-like CD1d-restricted T cells that have NK cell–like properties and bear an invariant T cell receptor (iTCR). iNKT cells have shown potential for cancer immunotherapy. A study now shows that stabilization of the iTCR–CD1d complex via a single-chain bi-specific antibody stimulates iNKT cell–mediated anti-tumor immunity.

Although RET alterations are relatively frequent across tumor types, specific targeting of RET in the clinic has been challenging. Ambrogio, Aggarwal and colleagues provide their views on how mechanistic studies have swiftly translated into powerful targeted therapies in two recent clinical studies that led to the FDA approval of selpercatinib for certain tumors in which RET is altered.

Beltran and colleagues discuss the challenges in treating metastatic prostate cancer and strategies to accelerate precision oncology and improve therapy and clinical decisions in this setting.

Tumor-specific changes in DNA methylation are both acquired actively through transcription-coupled processes and passively accumulated over time. Analysis across B cell malignancies now shows that these changes provide insight into the cellular origin as well as the proliferative history of tumors and thereby have diagnostic value and prognostic value, respectively.

Mitochondrial DNA damage, metabolic disruption and aging have all been associated with cancer. These three threads are now woven together to show that aging-associated somatic mutations to mitochondrial DNA alter mitochondrial serine metabolism to support cell transformation and colon-cancer development.

Effective methods for treating retinoblastoma while preserving vision are an unmet clinical need. Subretinal delivery of a hydrogel containing T cells that secrete the cytokine IL-15 and express a chimeric antigen receptor directed at the ganglioside protein GD2 completely controls retinoblastoma in immunocompromised mice, with no obvious damage to the surrounding retina.

Cancer has found a formidable foil in COVID-19, and this has brought to the fore the early concerns that COVID-19 could have a deeper impact on oncology patients. Two studies now provide insights into the enigma surrounding the determinants of the worsening of COVID-19 symptoms in patients with cancer.

Zitvogel and colleagues discuss the interplay between cancer and COVID-19 with respect to patient risk and prognosis, immune responses and potential therapies.