Immunotherapy is standard of care for many malignancies, including non-small cell lung cancer, but its benefits have not extended to pancreatic cancer. In this issue of Cancer Cell, DeNardo and colleagues investigate the differences in immune response in lung and pancreas and potential approaches to overcome immunoresistance in the latter.

In this issue of Cancer Cell, Xiong and colleagues describe the genomic and transcriptional landscape of natural killer/T cell lymphoma (NKTCL), a rare form of non-Hodgkin’s lymphoma associated with EBV infection. They divide NKTCL into molecularly defined subtypes that could inform therapeutic strategies for patients with this deadly disease.

Chemotherapy remains the main treatment option for patients with several tumor types. In this issue of Cancer Cell, Salvador-Barbero et al. demonstrate that treatment with CDK4/6 inhibitors after application of taxanes (or other chemotherapeutic compounds) strongly potentiates the anti-tumor effect due to repression of DNA repair machinery.

Several acute myeloid leukemia genetic sub-types converge on high expression of HOX genes, critical for their self-renewal. A new orally bioavailable Menin-MLL inhibitor (VTP-50469) appears to promote their differentiation through direct effects on the HOX cofactor MEIS1, paving the way for clinical trials.

N6-Methyladenosine (m6A) RNA modification has emerged in recent years as a new layer of regulatory mechanism controlling gene expression in eukaryotes. As a reversible epigenetic modification found not only in messenger RNAs but also in non-coding RNAs, m6A affects the fate of the modified RNA molecules and plays important roles in almost all vital bioprocesses, including cancer development. Here we

PARP inhibition (PARPi) kills tumor cells defective in homologous recombination-based repair (HR-) but not their HR+ competent counterparts. In this issue of Cancer Cell, it is shown that, when EZH2 is functionally silenced, HR+, CARM1-high, high-grade serous ovarian cancer cells become PARPi sensitive, undergo mitotic catastrophe, and die.

The role of ROS in cancer is complex, with studies demonstrating both pro- and anti-tumor effects. In a pancreatic ductal adenocarcinoma model, ROS limitation through TIGAR has been shown to initially support cancer development but to later become a metabolic liability in metastasizing cells that is counteracted by decreased TIGAR expression.

CAR T cells with different costimulation domains have proven clinical efficacy in leukemia and lymphoma but have different kinetics of activation, antigen sensitivity, and susceptibility to exhaustion. Two recent studies identified that these functions are shaped by a balance among opposing signaling complexes and transcription factors competing for binding motifs.

For decades, scientists have observed small extrachromosomal DNA fragments in tumor cells, yet comprehensive examination of their structure and function has remained difficult. Three recent studies, published in Nature, Cell, and Nature Genetics, have now shed important light on the architecture, regulatory capacity, and oncogenic nature of tumor-associated extrachromosomal DNA.

Metabolic pathways must be adapted to support cell processes required for transformation and cancer progression. Amino acid metabolism is deregulated in many cancers, with changes in branched-chain amino acid metabolism specifically affecting cancer cell state as well as systemic metabolism in individuals with malignancy. This review highlights key concepts surrounding the current understanding of

The inter-differentiation between cell states promotes cancer cell survival under stress and fosters non-genetic heterogeneity (NGH). NGH is, therefore, a surrogate of tumor resilience but its quantification is confounded by genetic heterogeneity. Here we show that NGH in serous ovarian cancer (SOC) can be accurately measured when informed by the molecular signatures of the normal fallopian tube epithelium

Therapeutic resistance is a major challenge in cancer treatment. In this issue of Cancer Cell, Kurppa et al. demonstrated that a senescence-like state enables lung cancer cells to survive dual inhibition of EGFR and MEK. This was mediated by the YAP/TEAD pathway, which drives epigenomic reprogramming and EMT to counteract apoptosis.

Drugs that target KRAS 12C covalently, AMG 510 and MRTX849, are now in the clinic. Recent papers describe development of these compounds, their selectivity and properties, early clinical data, and potential combination therapies. These papers herald a new era in Ras research, with improved drugs and strategies certain to follow.

In a recent issue of Science, Russo et al. observe that colorectal cancer cells, when exposed to the pressure of EGFR- and BRAF-targeted therapies, transiently alter their transcriptional profiles to foster mutagenesis, thereby enhancing the stochastic development of acquired resistance mutations.

Metastatic cancer is a major cause of death and remains largely incurable. A better understanding of metastasis is therefore desperately needed to improve prognosis for late-stage disease. Here we survey the landscape of studies exploring the genomics of metastatic cancer. We consider evidence for genomic drivers of metastasis and explore studies investigating modes of metastatic spread.

Carcinogen-induced cancers typically have high mutation burdens and an inflamed microenvironment and thus are poised to respond to immune checkpoint inhibitors (ICIs). However, cancers with loss-of-function mutations in the SWI/SNF complex have few additional mutations yet also have an inflamed immunophenotype and should respond to ICI therapy.

There is increasing appreciation of the microbial influence on cancer, with emerging evidence about the tumor microbiome and crosstalk with the gut microbiome. A great example of this is pancreatic cancer, in which intra-tumoral microbes such as bacteria and fungi have been shown to contribute to carcinogenesis and therapeutic responses, both positively and negatively.

The combination of ipilimumab and nivolumab was evaluated versus standard treatments in melanoma and lung cancer. Analysis of these trials highlights the differences in outcomes and potential predictive biomarkers across tumor types as well as the multiple remaining questions concerning the optimal use of immune checkpoint inhibitors.

Adenosine is a key metabolic and immune-checkpoint regulator implicated in the tumor escape from the host immune system. Major gaps in knowledge that impede the development of effective adenosine-based therapeutics include: (1) lack of consideration of redundant pathways controlling ATP and adenosine levels; (2) lack of distinction between receptor-dependent and -independent effects of adenosine, and

Despite the role of STAT3 as a known driver of oncogenesis, efforts to develop therapeutic STAT3 inhibitors have thus far been unsuccessful. In this issue of Cancer Cell, Bai et al. report a potent and selective STAT3 degrader capable of producing complete and long-lasting tumor regression in mouse xenograft models.

In this issue of Cancer Cell, Quereda and colleagues report that a newly developed specific inhibitor of CDK12/13, SR-4835, sensitizes triple-negative breast cancer cells to PARP inhibitors and DNA-damaging chemotherapeutics by reducing expression of the genes in the DNA damage response pathway.

In this issue of Cancer Cell, Pillarsetty and colleagues radiolabel the potential anticancer drug PU-H71 and use it with PET imaging to quantify the epichaperome protein complex in tumors and its inhibition by the drug. They thereby develop a companion diagnostic paradigm of probe-drug pairing to explore therapeutic potential.

Immunotherapy has been the most effective in tumors with high mutational burden. However, a recent study in Cell by Wolf et al. demonstrates that high intratumor heterogeneity (ITH) for cancer neoantigens paradoxically attenuates anti-tumor immune responses, suggesting a need to quantify ITH to improve patient selection for checkpoint blockade therapy.

Stress has long been suspected to negatively influence cancer mortality, yet the molecular mechanisms responsible for this effect have only recently been identified. A new study identifies a stress-induced response in dendritic cells—the activation of the glucocorticoid-inducible transcriptional regulator TSC22D3—as a potent, immunosuppressive effect of stress on cancer.

Checkpoint blockade (CPB) therapy can elicit durable clinical responses by reactivating an exhausted immune response. However, response rates remain limited, likely secondary to a lack of a tumor-reactive immune infiltrate. Chimeric antigen receptor (CAR) T cells may provide the necessary tumor-targeting immune infiltrate and a highly specific antitumor immune response. This can be further amplified

In this issue of Cancer Cell, Guièza et al. describe that overexpression of the pro-survival protein MCL1 and cellular energy metabolic reprogramming can contribute to resistance to the BCL2 inhibitor venetoclax in patients with chronic lymphocytic leukemia. This adds a new dimension to understanding of secondary clinical resistance to venetoclax.

In this issue of Cancer Cell, Burr et al. report that PRC2 plays a conserved role in silencing antigen presentation and processing genes and, in turn, CD8+ T cell activation. Furthermore, PRC2-targeted therapeutics overcome gene silencing and promote tumor clearance by cytotoxic T cells.

Mechanisms of acquired resistance to ALK inhibition therapy in neuroblastoma have not yet been elucidated. In a recent issue of Nature, Debruyne et al. demonstrate that resistant MYCN-amplified ALK-mutated neuroblastoma cells overexpress BORIS, resulting in wide-ranging changes in chromatin interaction and transcriptional reprogramming.