Reviews & Analysis

Immunosuppressive myeloid cells, which are associated with resistance to anti-PD1 therapy in patients with glioblastoma, have high expression of KDM6B, an epigenetic enzyme. Deletion or inhibition of KDM6B reprograms the myeloid cells to an immunostimulatory phenotype and thereby overcomes resistance to anti-PD1 therapy in preclinical models of glioblastoma.

In this Review, Konstantinopoulos and Matulonis discuss recent clinical advances in the treatment of ovarian cancer and reflect on persisting challenges.

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.

Treatment with immune checkpoint inhibitors (ICIs) has improved the survival of patients with metastatic melanoma. However, although ICIs are promising for achieving lasting clinical responses, only a subset of patients receive substantial benefit. Our results suggest that the IL-17 pathway supports the response of melanoma to dual ICI therapy and might represent a biomarker for patient stratification.

This study reveals the previously underappreciated roles of CD25 (IL-2 receptor subunit-α) in IL-2 biology and cancer immunotherapy and provides mechanistic insights into the rational design of more-effective IL-2-based therapeutic agents for cancer treatment.

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.

Blanpain and colleagues review the current knowledge on cancer cell plasticity and its impact on tumor initiation and progression, the metastatic cascade and resistance to therapy.

Sears and colleagues discuss the latest advances in the understanding of host and microbiota mechanisms involved in the relationship between the microbiome and cancer and emerging avenues for applying these insights to cancer therapy.

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.

Brastianos and colleagues discuss the molecular and microenvironmental features of brain metastases, as well as promising avenues in translational research to overcome challenges for effective treatments.

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.

Tyrosine kinase inhibitors that target anaplastic lymphoma kinase (ALK) have greatly improved the survival of patients with ALK-rearranged non-small-cell lung cancer, but they are insufficient to achieve a complete cure. A newly developed vaccine elicited a strong immune response specifically against ALK that eradicated primary tumors and prevented the onset of metastatic disease in mice.

Samuels and colleagues review the landscape of cancer peptide antigens, focusing on emerging concepts and the latest translational and clinical advances.

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.

Chimeric antigen receptor (CAR) T cells are effective for the treatment of therapy-resistant blood cancers but not solid tumors. We used a well-studied mutant c-KIT protein (c-KIT D816V) as a co-stimulatory domain to generate CAR T cells with strong IFNγ signaling that were able to overcome the immunosuppressive microenvironment of solid tumors.

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.

Green and colleagues discuss modes of cell death in cancer and focus on ‘near-death experiences’, whereby tumor cells engage the regulated cell death machinery yet survive, with far-reaching consequences for tumor survival, growth and therapy.