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  • 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.

    • Ryan B. Corcoran
    News & Views
  • 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.

    • Lauren M. Harmon
    • Timothy J. Triche Jr
    News & Views
  • 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.

    • Christopher E. Rudd
    News & Views
  • 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.

    • Thomas U. Marron
    • Jennifer L. Guerriero
    News & Views
  • 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.

    • Ashley N. Anderson
    • Summer L. Gibbs
    News & Views
  • 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.

    • Seth B. Coffelt
    • Toshiyasu Suzuki
    News & Views
  • 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.

    • Alessia Mira
    • Chiara Ambrogio
    News & Views
  • 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.

    • Helene Damhofer
    • Kristian Helin
    News & Views
  • 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.

    • Dietmar Rieder
    • Zlatko Trajanoski
    News & Views
  • 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.

    • M. Eric Kohler
    • Terry J. Fry
    News & Views
  • 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.

    • Paul A. Stewart
    • Alex M. Jaeger
    News & Views
  • 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.

    • Martina Semenzato
    • Luca Scorrano
    News & Views
  • 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.

    • Stanislav Drapela
    • Ana P. Gomes
    News & Views
  • 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.

    • Philip Bucher
    • Judith Feucht
    News & Views
  • 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.

    • Paul J. Neeson
    • Paul G. Ekert
    News & Views
  • Clinical utility of T cell engagers (TCEs) in cancer immunotherapy for solid tumors is hampered by on-target off-tumor activity and dose-limiting adverse events. A study now proposes a solution to tackle these challenges through the design and preclinical characterization of extended half-life TCEs that are conditionally activated in the tumor microenvironment.

    • Aliyah B. Silver
    • Jeremy Wang
    • Jamie B. Spangler
    News & Views
  • Although targeting cancer cells on the basis of tissue-specific expression of key factors is an important strategy in precision oncology, few such therapies exist. Chemical screening now identifies YC-1 as a tissue-specific anti-cancer compound that is activated in the liver by the sulfotransferase enzyme SULT1A1.

    • Zixi Wang
    • Hao Zhu
    News & Views
  • Transactivation hubs and related biomolecular condensates are emerging as relevant molecular players in cancer biology. A new study now links PD-L1 upregulation on the cancer cell surface and IRF1–KAT8 transactivation hubs at PD-L1 loci. Therapeutic targeting of these hubs holds potential to unleash antitumor immunity.

    • Kelsey P. Kubelick
    • Felipe Garcia Quiroz
    News & Views
  • Patients with blood cancer have fewer antibodies after SARS-CoV-2 vaccination — but recent work shows that these antibodies seem to bind to viral spike protein more strongly than those in matched controls. In addition, another study finds that convalescent or vaccinee plasma might improve COVID-19 outcomes in those with blood cancer.

    • Ratna Wijaya
    • Sean H. Lim
    News & Views
  • Acute myeloid leukemia (AML) is a heterogeneous disease with poor prognosis and treatment options. A new study reveals a unique inflammatory signature in pediatric and adult AML malignant cells that is associated with the infiltration of atypical B cells in the bone marrow microenvironment, which adds an independent layer of prognostic information.

    • Asaf D. Yanir
    • Shai Izraeli
    News & Views