News & Views in 2023

Transmissible cancer affects marine bivalve mollusks worldwide, but how genetic mechanisms influence cancer evolution and disease spread remains largely unexplored. Two new studies provide insights into the ancient origin of founder clones and the long-term tolerance of contagious cancer cells to extreme genome instability.

Chimeric antigen receptor T cells and T cell-redirecting bispecific antibody therapies are changing the landscape of myeloma therapy. Two studies investigate the genetic and epigenetic resistance mechanisms that lead to relapse in patients receiving T cell-engaging therapies targeting B cell maturation antigen (BCMA) and GPRC5D.

Certain cancers disrupt metabolism, leading to the wasting syndrome known as cachexia. How tumor-induced mediators of cachexia induce changes in end organs is unclear. A study implicates the endothelium as an amplifier of tumor signals in fat, in which NOTCH1 promotes adipose tissue remodeling via retinoic acid, IL-33 and IGFBP3.

The nervous system regulates cancer progression, and the importance of neuron–glioma communication in tumor growth is evident in glioblastoma. This tumor-promoting communication presents a potential therapeutic axis, a concept reinforced by a study that identifies a specific potassium channel complex as a therapeutic target.

The development of immunotherapies for acute myeloid leukemia (AML) has been limited by a lack of known tumor-specific targets. A study now shows the feasibility of developing highly sensitive and selective T cell-receptor-based therapies against an HLA-A*02:01-associated peptide derived from a recurrent mutation in a subset of patients with AML.

The recent design of mutation-selective KRAS inhibitors has led to US Food and Drug Administration approval of two inhibitors of KRAS(G12C), sotorasib and adagrasib. A study published in Nature reports the development of a first-in-class pan-KRAS-selective inhibitor. Here we comment on the current status of KRAS-targeting approaches.

The advantage of genomic monitoring over cytogenetics for clinical assessment of leukemia is illustrated by a case of pediatric acute lymphoblastic leukemia in which a lesion underlying lethal end-stage myeloid disease could be detected by whole-genome sequencing years before the risk manifested cytogenetically.

CD8⁺ T cells recognize tumor-associated antigens presented by major histocompatibility complex (MHC) class I molecules. How CD8⁺ T cells eliminate cancer cells deficient in MHC class I has been unclear. A study now shows that adaptive CD8⁺ T cell activation induces expression of the innate receptor NKG2D for the elimination of MHC class I–deficient tumors.

Glioblastoma is an aggressive brain tumor with a highly immunosuppressive environment that responds poorly to immune checkpoint inhibitors. A study shows that SIGLEC9⁺ monocyte-derived macrophages are enriched in glioblastomas that do not respond to immune checkpoint inhibitors, and targeting this receptor synergizes with immunotherapy.

Pathological diagnosis relies on morphological assessment of tissue using histological staining and molecular phenotyping through immunostaining that must be performed on separate tissue sections. Orion is a newly reported methodology that facilitates multiplexed immunostaining with histological staining on the same slide.

Distinct subsets of γδ T cells that operate to either prevent or promote cancer progression have been characterized in mice. A study now indicates that human tumor-infiltrating γδ T cells also are more diverse than previously appreciated, consisting of functionally distinct subsets with tumor-promoting or -restricting functions.

The discovery and approval of direct KRAS inhibitors for clinical use showed that mutant KRAS is not, as previously thought, an ‘undruggable’ oncoprotein. But therapeutic success is limited by the rapid onset of resistance. Two studies now show that YAP and TAZ represent an actionable target for tackling adaptive resistance to KRAS inhibitors.

Successful immune-mediated tumor control in pancreatic cancer is severely hampered by its dense desmoplastic stroma. New work shows that EZH2 inhibition relieves the suppressive effect of tumor stroma on pro-inflammatory chemokine expression after therapy-induced senescence, boosting NK and T cell recruitment and immunological tumor control.

Given the increasing use of immune-checkpoint inhibitors for treating cancer, immune-related adverse events — and markers to prevent and diagnose these — are coming into focus. A systematic analysis investigates genetic, molecular, cellular and clinical risk factors of such adverse events in a large pan-cancer cohort treated with multiple agents.

Therapeutic products containing CD8⁺ and CD4⁺ T cells expressing CARs are effective at inducing remission in patients with cancer. How CD4⁺ CAR T cells contribute to the anti-tumor response has not been well established. A study uses syngeneic models and in vivo imaging to glean mechanistic insights into how CD4⁺ T cells target tumors.

Antigen presentation is fundamental to anti-tumor immunity, but our understanding of the physiological and molecular inputs to the process in different contexts remains limited. Two new studies explore the contribution of cell-intrinsic proteolytic mechanisms and cell-extrinsic hot and cold tumor microenvironments in shaping the antigenic landscape in lung cancer.

Glioblastomas have limited treatment options and dire prognoses. A study now shows that GAP43-mediated transfer of functional mitochondria from astrocytes to glioblastoma cells leads to metabolism, signaling and epigenome remodeling that favor tumor growth, thus highlighting GAP43 inhibition as a promising therapeutic strategy for glioblastoma.

As we age, organs undergo architectural and functional changes that deeply affect the fate of disseminated tumor cells (DTCs). A study now adds further complexity to this picture by revealing a role for the age-induced, fibrosis-associated factor PDGF-C in enabling ER⁺ DTCs to reawaken in aging lungs and thrive as overt metastasis.

The lack of tumor-specific surface antigens has limited the application of CAR T cells in solid tumors. A new AND-gated CAR T cell system repurposes proximal T cell signaling proteins to restrict activation to dual antigen encounter, mitigating on-target, off-tumor toxicity while preserving antitumor efficacy in preclinical models.

The response rates of pediatric cancers to immune checkpoint inhibitor therapies are disappointingly low, particularly when compared to the remarkable impact of these drugs in many adult cancers. A new study leverages clinical trial data to identify biomarkers that might improve patient selection in future clinical trials.