In This Issue

See article, p. 47.

RAS/ERK pathway inhibitors are used frequently in NSCLC therapy, yet how they affect the tumor immune microenvironment has remained unclear. Tang, Li, and colleagues studied the immunomodulatory effects of SHP2 inhibitors, recently shown to be active against select KRAS-mutant tumors. SHP2 inhibitors depleted alveolar and M2-like macrophages and promoted B and T lymphocyte infiltration, all salutary therapeutic effects. However, they also increased intratumor gMDSCs via tumor-intrinsic, NFκB-dependent production of CXCR2 ligands. Other RAS/ERK pathway inhibitors had similar effects in mouse and human models. Combined SHP2/CXCR1/2 inhibition depleted a specific gMDSC subset, reactivated select antitumor T cells, and improved survival.

See article, p. 62.

Persistent COVID-19 infection in patients with cancer has been reported, but the drivers of this clinical phenomenon are unknown. Lee and colleagues report that B-cell lymphomas were at particularly high risk for persistent SARS-CoV-2 positivity. Further analysis of these patients identified active therapy and diminished T-cell counts as drivers of acute mortality in COVID-19 infected patients with lymphoma, while B cell–depleting therapy was the primary driver of chronic infection. In patients with persistent SARS-CoV-2 positivity, high levels of viral entropy were observed consistent with intrahost viral evolution, particularly in patients with impaired CD8⁺ T-cell immunity.

See article, p. 74.

Resistance to EGFR tyrosine kinase inhibitors (TKI) presents a continuous challenge in non–small cell lung cancer (NSCLC). HER3 is a receptor tyrosine kinase overexpressed in EGFR-mutant NSCLC; however, it remains unknown whether targeting HER3 can overcome EGFR TKI resistance. Jänne and colleagues conducted a phase I clinical trial of the HER3 antibody drug conjugate patritumab deruxtecan (HER3-DXd) in patients with advanced or metastatic NSCLC. This study showed prolonged progression-free survival in patients treated with HER3-DXd as well as a manageable safety profile, supporting a further phase II study in patients with NSCLC who progress after EGFR TKI therapy.

See article, p. 90.

Fasting-mimicking diet (FMD) is a plant-based, calorie-restricted, low-carbohydrate, low-protein diet repeated cyclically every 3 to 4 weeks. Vernieri and colleagues investigated 101 patients who underwent cyclic five-day FMD in combination with their standard antineoplastic therapies. The FMD was safe and well tolerated and reduced blood glucose, insulin, and insulin-like growth factor levels. In addition, the FMD boosted the immune system by reducing immunosuppressive cells and increasing activated and cytotoxic immune cells in both peripheral blood and the tumor microenvironment. This study lays the foundation for investigating the antitumor efficacy of cyclic FMD in combination with standard antitumor therapies in selected patient cohorts.

See article, p. 108.

The development of noninvasive and nontoxic approaches to improve T-cell infiltration into tumors could enhance immunotherapy response. Herrera and colleagues demonstrated low-dose radiotherapy (LDRT) in advanced ovarian cancer can render it responsive to combinatorial immunotherapy. LDRT attracted T lymphocytes, including a large proportion of CD4⁺ T cells presenting a cytolytic phenotype and expressing NKG2D, when combined with immunotherapy. Single-cell RNA sequencing revealed combination treatment also reprogrammed the myeloid compartment, generating a distinct subset of dendritic cells expressing the NKG2D ligand, RAE1. The ability of LDRT to harness adaptive and innate immunity to promote immunotherapy response was also demonstrated in a phase I clinical trial.

See article, p. 134.

Liver metastasis of colorectal cancer harbors a heterogeneous and immunosuppressive microenvironment, but how this is orchestrated remains incompletely understood. Wu, Yang, Ma, Chen, and colleagues sequenced 97 samples using single-cell RNA sequencing and spatial transcriptomics to trace immune cell evolution during metastasis. MRC1⁺ CCL18⁺ M2-like macrophages were strongly enriched and were metabolically activated within the metastatic site. Chemotherapy-responsive samples showed the depletion of such immunosuppressive cells and was accompanied by an increase of cytotoxic CD8⁺ T cells. These data uncover the spatiotemporal immune landscape of colorectal cancer liver metastasis and open opportunities for designing novel strategies against metastasis.

See article, p. 154.

The extensive intratumoral genomic heterogeneity of glioblastoma (GBM) has been well-documented and is frequently linked to treatment resistance. However, the extent to which this heterogeneity impacts the local immune microenvironment and how it compares between primary gliomas and secondary brain metastases is unclear. Utilizing multisector analysis, Schaettler, Richters, and colleagues comprehensively profiled the genomic and immunologic state of a cohort of gliomas and brain metastases. Between the two tumor types, gliomas harbored significantly greater heterogeneity at the genomic and neoantigen level. The intratumoral T-cell repertoire was similarly distributed, with many gliomas containing highly regionally expanded T-cell clones.

See article, p. 172.

Oncogenic mutations exist in several nondiseased human organs. Still, their prevalence and patterns in the human brain remain unknown. Using two orthogonal methods and screening large cohorts of nondiseased human brains, from fetal to old ages, Ganz, Maury, and colleagues discovered the existence of pathogenic somatic single-nucleotide and copy number variants. These mutations had high allele frequency representing macroscopic clones, were enriched in the brain's white matter, and were less frequent in older individuals. The patterns of mutations observed in the normal brain were similar to those in brain tumors, suggesting that normal mutational processes drive early brain oncogenesis.

See article, p. 186.

To uncover the mechanism underlying relapse of pediatric acute lymphoblastic leukemia (ALL) associated with an activating mutation of the histone methyltransferase NSD2, Li and colleagues performed throughput drug screening of NSD2-mutant cells, finding them to be resistant to glucocorticoids. This was due to depressed transcription of NR3C1 encoding the glucocorticoid receptor (GR) and the aberrant presence of repressive H3K27me3 at its promoter, preventing autoactivation of GR expression by glucocorticoids. Treatment with PRC2 inhibitors increased GR levels and restored autoactivation, genome-wide GR binding, and activation of proapoptotic BIM, suggesting a new therapeutic approach for relapsed ALL with mutant NSD2.

See article, p. 204.

Despite several inhibitors of PI3K being in clinical trials, the efficacy of these in patients with PIK3CA mutations remains modest. Song and colleagues therefore sought to improve upon the therapeutic index through identification of compounds that demonstrated increased mutant p110α specificity. One such inhibitor, GDC-0077, was found to potently inhibit the mutant PI3K pathway through HER2-dependent mutant p110α degradation and was more effective at prolonging pathway suppression. This study provides a rationale for pursuing degraders of PI3Kα as well as establishes a strategy for identification of inhibitors that target mutants in tumors for selective degradation.

See article, p. 220.

To deliver on the promise of personalized cancer therapy, it is necessary to uncover the significance of novel pathogenic variants. DNMT3A has emerged as one of the most important tumor suppressors in the hematopoietic system, with mutations frequently found in clonal hematopoiesis as well as myeloid and lymphoid malignancies. Huang and colleagues functionally profiled most known patient-associated DNMT3A variants, discovering a large subset with dramatically reduced protein stability. Unstable mutants, as a class, were associated with greater clonal expansion and increased likelihood of cancer development. A CRISPR/Cas9-based screen uncovered essential components of DNMT3A protein turnover which may lead to new therapeutic interventions.

See article, p. 236.

The impact of transient bacterial infection on long-term colon tumorigenesis has not been carefully examined. Liu, Fu, and colleagues revealed that a group of enteric pathogens, that is, attaching/effacing (A/E) bacteria, utilize the Type 3 Secretion System to inject genotoxin (UshA) into infected enterocytes during their transient and noninvasive infections. Conferred by the enzymatic activity of UshA, A/E pathogen infection elicits DNA double-strand breaks in infected host cells, causing transformative changes and accelerating colon tumorigenesis in mice. Moreover, mutational signature characterization of mouse colon tumors underscores that A/E pathogen infection-introduced mutations are associated with human colon cancer etiology.

See article, p. 250.

Myelodysplastic syndromes (MDS) are one of the most complex hematopoietic stem cell (HSC) malignancies, characterized by ineffective hematopoiesis in which clonal progenitor expansion coexists with impaired myelopoiesis and excessive cell death. However, little is known about the pathobiological mediators of ineffective hematopoiesis in MDS. Aoyagi and colleagues identified DRP1-mediated mitochondrial fragmentation in HSCs/progenitors of mice and patients with MDS regardless of mutational profile. Importantly, inhibition of mitochondrial fragmentation attenuated inflammatory signaling activation, rescued ineffective hematopoiesis phenotype, and prolonged survival of MDS mice, suggesting that overwhelming mitochondrial fragmentation could be a fundamental trigger of MDS pathogenesis.