Reviews & Analysis

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.

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.

Rebbeck, Huang and colleagues discuss recent insights into health inequities related to clinical next-generation sequencing for precision oncology, the contributing factors as well as recommendations for resolution looking ahead.

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.

An antisense RNA, NQO1-AS, binds and stabilizes its sense strand, upregulating the redox enzyme NQO1 in metastatic breast cancer cells. Overexpression of NQO1 facilitates lung colonization by suppressing oxidative stress and ferroptosis, and cancer cells dependent on this pathway can be targeted by a combined therapy that induces ferroptosis while simultaneously inhibiting NQO1.

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.

Glioblastomas are aggressive primary brain tumors with an inherent resistance to T cell-centric immunotherapy. We examined the dynamic changes of immune cells that occur in the tumor microenvironment of radio-immunotherapy-treated glioblastomas and identified a subpopulation of regulatory T cells with increased immunosuppressive activity. Depletion of this cell population improved survival in a mouse model of glioblastoma.

Multiple myeloma is a rare and incurable cancer of plasma cells. To characterize this cancer, we developed an ex vivo drug screening method that combines imaging, deep learning and multiomics and applied it in an observational trial, uncovering new potential therapeutic strategies and underlying disease mechanisms.

Kimmelman and colleagues discuss the role of autophagy in tumor cells and of cell-nonautonomous autophagy in the microenvironment and host cells in supporting tumor growth and reflect on open questions in the field.