In this issue of Cancer Cell, Zaitsev et al. (2022) present a machine-learning-based approach, trained from millions of artificial transcriptomes with admixed cell populations, for reconstructing tumor microenvironments (TMEs). The high accuracy of this approach, demonstrated through extensive validation, enables systematic investigation of TMEs in both research and clinical settings.

Metastasis, the major cause of cancer death, represents one of the major challenges in oncology. Scientists are still trying to understand the biological basis underlying the dissemination and outgrowth of tumor cells, why these cells can remain dormant for years, how they become resistant to the immune system or cytotoxic effects of systemic therapy, and how they interact with their new microenvironment

Pancreatic ductal adenocarcinoma is characterized by a complex microenvironment. In this issue of Cancer Cell, Chen and colleagues define an oncogenic role of tumor-cell-produced collagen I homotrimers, wherein tumor development is promoted by integrin α3/β1-dependent activation of tumor cell signaling and modulation of tumor microbiome and immunity.

Morphology, immunophenotype, cytogenetics, and genomics have long dominated diagnostics in acute myelogenous leukemia (AML). In this issue of Cancer Cell, Bottomly et al. demonstrate that combining the above with transcriptomics and ex vivo drug testing of patient myeloblasts yields novel diagnostic and therapeutic insights with the potential for clinical translation.

Meaningful integration of artificial intelligence (AI) will transform the application of “big data” for patient care, diagnosis, and research. In this issue of Cancer Cell, Chen et al. describe a transparent system to integrate histopathology and molecular data to predict outcomes and identify novel biomarkers in cancer.

Transposable elements (TEs), which make up almost half of the human genome, often display altered expression in cancers. Here, we review recent progress in elucidating the role of TEs as mediators of immune responses in cancer and discuss how novel therapeutic strategies can harness TE immunogenicity for cancer immunotherapy.

In a recent publication in Nature, Fane et al. establish WNT5A as a central, age-sensitive regulator of the dormancy-to-reactivation axis of melanoma. They show that aged fibroblasts in the lungs suppress WNT5A signaling induced at the primary tumor site to awaken dormant melanoma cells and promote the outgrowth of metastases.

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A Cell article reports that lymph node metastases can suppress the immune system, thereby promoting further cancer spread in mouse models; this is corroborated in patients as described in a letter in this issue of Cancer Cell. The lymph node thus actively generates a cancer-permissive environment and is an untapped target to manipulate the immune system.

EGFR exon 20 insertions represent a subgroup of NSCLC patients posed with a therapy dilemma. In this issue of Cancer Cell, Elamin and colleagues demonstrate that only insertions localized in the near loop respond to poziotinib. Pharmacological inhibition of spindle assembly checkpoint components inhibits tumor growth in poziotinib-resistant exon 20 insertions.

In this issue of Cancer Cell, Belk et al. perform an in vitro CRISPR screen to identify genes that regulate CD8+ T cell exhaustion. They find several genes related to epigenetic modification and show that by eliminating Arid1a, CD8+ T cells retain proliferative and cytotoxic function in vivo, leading to better anti-tumor activity.

Immunoediting, the loss of tumor (neo)antigens due to T cell-dependent selection, sculpts tumor immunogenicity. In Nature, Łuksza et al. conceive a model to score neoantigens’ immunogenicity and predict tumor clonal evolution. With this model, they demonstrate that durable tumor control associates with selective limited acquisition of high-quality mutations.

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In this issue of Cancer Cell, Kurz et al. demonstrate in an orthotopic pancreatic cancer model that low-intensity exercise improves tumor control and response to immunotherapy in an IL-15-dependent manner. Combination therapy, IL-15 super-agonist, anti-PD-1 antibody and chemotherapy, strongly reduces tumor growth. Therefore, the study opens rich translational avenues.

Recent evidence highlights patients’ sex relevance in antitumor immune response through a complex interaction—among hormones, genes, behaviors, and the microbiome—that affects both innate and adaptive immune functions, as well as immune evasion mechanisms. These complex interactions ultimately influence the efficacy and toxicity of immune checkpoint inhibitors in solid tumors.

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In Nature, Chou et al. identify a subset of innate-like αβ T cells with high cytotoxic potential that accumulate in tumors and elicit an anti-tumor response. Given their capacity to maintain an activation state without undergoing exhaustion, these innate-like T cells may represent effective therapeutic agents for cell-based approaches.

Given the renewed interest in vaccine development sparked by the COVID-19 pandemic, we are revisiting the current state of vaccine development for cancer prevention and treatment. Experts discuss different vaccine types, their antigens and modes of action, and where we stand on their clinical development, plus the challenges we need to overcome for their broad implementation.

The therapeutic landscape of breast cancer is becoming increasingly complex. In this issue of Cancer Cell, Wolf et al. present a breast cancer classification scheme that allows for better prediction of treatment response and can be continuously adapted to guide prioritization of new treatments.

The microbiome has a major impact on tumor progression, yet the mechanisms are poorly defined. Fu et al. report in Cell that intracellular bacteria in a breast cancer model promote metastasis via reorganizing the cytoskeleton to enhance resistance to mechanical stress, thereby facilitating survival in the circulation during dissemination.

In a recent Science study, an advanced mutational signature analysis was performed on an unprecedentedly large set of cancer whole-genome sequences across multiple organs. This work introduces a computational framework to identify common and rare mutational signatures and provides insights into their biological interpretation.

The CheckMate 649 trial, recently published in Nature, established chemotherapy plus nivolumab as a standard in advanced, treatment-naive gastroesophageal adenocarcinoma, with best results seen in patients with high PD-L1 expression and microsatellite unstable tumors. In contrast, nivolumab plus ipilimumab, compared with chemotherapy, showed early progression and no overall survival benefit.

The results of the most recent Checkmate-816 trial in The New England Journal of Medicine using combination neoadjuvant immunotherapy with platinum-based chemotherapy in resectable non-small cell lung cancer demonstrate the effectiveness of neoadjuvant immunotherapy and provide further support that biology and personalized therapy represent the foundation of lung cancer treatment.

In this issue of Cancer Cell, Huang et al. identify the origin and function of a subset of pancreatic cancer-associated fibroblasts. This work further highlights the power of lineage-tracing models for dissecting the tumor microenvironment in pancreatic cancer and provides new knowledge toward the development of novel therapeutic strategies.

In this issue of Cancer Cell, Long et al. demonstrate that tumors can reprogram erythroid progenitors into myeloid-erythroid cells that promote immunosuppression. Erythroid-differentiated myeloid cells (EDMCs) expand in cancer-bearing individuals, resemble the functionality of myeloid-derived suppressor cells (MDSCs), and correlate with poor response to immune-checkpoint inhibitors (ICIs) and tumor-related

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Animal models have evolved to be a key component of translational research of cancer, and they are now extensively used to test drug candidates, predict drug responses, and essentially drive discovery of cancer biology. However, the model-centric approach has not yielded the expected abundance of treatment advances. We propose that the focus of translational research needs to shift from animal models

In this issue of Cancer Cell, Hanada et al. leverage single-cell multi-omics of lung cancer resident lymphocytes to identify phenotypic and transcriptomic signatures differentially expressed by neoantigen-reactive clonotypes. These findings could substantially expedite the selection of neoantigen-specific T cell receptors (TCRs) for individualized T cell therapies.

Increasing the efficacy of immune checkpoint blockade therapy while mitigating toxicity is one of the major challenges in oncology research. In this issue of Cancer Cell, Hailemichael et al. provide a strong rationale for the combination of IL-6 blockade and dual inhibition of CTLA-4 and PD-1 to overcome this issue.

In this issue of Cancer Cell, Anadon et al. perform a multi-omics analysis of ovarian tumor infiltrating tissue-resident memory T (TRM) cells at the single-cell level that supports a differentiation model from CD103−TCF1+ re-circulating T-cell precursors driven by tumor antigen recognition. CD103+ TRM cells play a dominant anti-tumor role in ovarian cancer.

Immune checkpoint inhibitors (ICIs) have limited activity in patients with castration-resistant prostate cancer (CRPC). A Nature article demonstrates that androgen receptor (AR) negatively modulates CD8+ T cell-driven antitumor immune response and that androgen-axis blockade is a promising therapeutic strategy to improve ICI activity in CRPC.

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The translational challenges in the field of precision oncology are in part related to the biological complexity and diversity of this disease. Technological advances in genomics have facilitated large sequencing efforts and discoveries that have further supported this notion. In this review, we reflect on the impact of these discoveries on our understanding of several concepts: cancer initiation,

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The success of chimeric antigen receptor (CAR) T cell therapy in solid tumors, unlike in hematologic malignancies, is limited by inadequate tumor infiltration and T cell dysfunction and exhaustion. Regional delivery of CAR T cells in patients with solid tumors is safe and feasible; promotes infiltration, proliferation, and trafficking; and ignites functionally persisting systemic immunity.

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Two papers published in this edition of Cancer Cell (Zheng et al., 2022 and Veatch et al., 2022) provide an elegant illustration of how single-cell sequencing can be used to define a molecular phenotype which identifies tumor-specific T cells.