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Single-cell technologies have revealed the complexity of the tumour immune microenvironment with unparalleled resolution 1 – 9 . Most clinical strategies rely on histopathological stratification of tumour subtypes, yet the spatial context of single-cell phenotypes within these stratified subgroups is poorly understood. Here we apply imaging mass cytometry to characterize the tumour and immunological landscape of samples from 416 patients with lung adenocarcinoma across five histological patterns. We resolve more than 1.6 million cells, enabling spatial analysis of immune lineages and activation states with distinct clinical correlates, including survival. Using deep learning, we can predict with high accuracy those patients who will progress after surgery using a single 1-mm 2 tumour core, which could be informative for clinical management following surgical resection. Our dataset represents a valuable resource for the non-small cell lung cancer research community and exemplifies the utility of spatial resolution within single-cell analyses. This study also highlights how artificial intelligence can improve our understanding of microenvironmental features that underlie cancer progression and may influence future clinical practice. Using imaging mass cytometry, the tumour and immunological spatial landscapes of 416 lung adenocarcinomas are characterized, which, when combined with deep learning, can predict clinical outcomes with high accuracy.

Therapies targeting the tumor microenvironment show promise for treating cancer. For example, antibodies targeting colony-stimulating factor-1 receptor (CSF-1R) inhibit protumorigenic macrophages and regress tumors in mouse models of glioblastoma multiforme (GBM), a deadly form of brain cancer. Quail et al. found that although CSR-1R blockade prolonged survival in mouse models of GBM, more than 50% of tumors eventually recurred. Recurrence was correlated with elevated PI3-K activity in tumors, driven by macrophage-secreted IGF-1. Blocking PI3-K and IGF-1 signaling in rebounding tumors prolonged survival. Thus, tumors can acquire resistance to therapy through intrinsic changes and through changes in their microenvironment. Science , this issue p. 10.1126/science.aad3018 Brain tumors can acquire resistance to therapy through changes to their microenvironment. Macrophages accumulate with glioblastoma multiforme (GBM) progression and can be targeted via inhibition of colony-stimulating factor–1 receptor (CSF-1R) to regress high-grade tumors in animal models of this cancer. However, whether and how resistance emerges in response to sustained CSF-1R blockade is unknown. We show that although overall survival is significantly prolonged, tumors recur in >50% of mice. Gliomas reestablish sensitivity to CSF-1R inhibition upon transplantation, indicating that resistance is tumor microenvironment–driven. Phosphatidylinositol 3-kinase (PI3K) pathway activity was elevated in recurrent GBM, driven by macrophage-derived insulin-like growth factor–1 (IGF-1) and tumor cell IGF-1 receptor (IGF-1R). Combining IGF-1R or PI3K blockade with CSF-1R inhibition in recurrent tumors significantly prolonged overall survival. Our findings thus reveal a potential therapeutic approach for treating resistance to CSF-1R inhibitors.

Obesity-associated inflammation promotes tumor growth and metastatic spread Obesity is a growing global epidemic and rivals smoking as the leading preventable risk factor for cancer incidence and mortality, being responsible for an estimated ∼20% of cancer-related deaths in adults ( 1 ). Obesity underlies a number of distinct but interconnected health conditions that have profound consequences for physiology, including hypernutrition, dysbiosis, hypercholesterolemia, metabolic syndrome, and chronic inflammation. Although each of these health conditions may affect cancer pathogenesis, inflammation, in particular, is known to be a potent driver of cancer initiation and progression through its ability to cultivate a microenvironment that is permissive to neoplastic transformation. Thus, as immuno-oncology continues to gain clinical importance, understanding the relationship between cancer and various inflammatory conditions, including obesity, is critical.

Obesity is associated with chronic, low-grade inflammation, which can disrupt homeostasis within tissue microenvironments. Given the correlation between obesity and relative risk of death from cancer, we investigated whether obesity-associated inflammation promotes metastatic progression. We demonstrate that obesity causes lung neutrophilia in otherwise normal mice, which is further exacerbated by the presence of a primary tumour. The increase in lung neutrophils translates to increased breast cancer metastasis to this site, in a GM-CSF- and IL5-dependent manner. Importantly, weight loss is sufficient to reverse this effect, and reduce serum levels of GM-CSF and IL5 in both mouse models and humans. Our data indicate that special consideration of the obese patient population is critical for effective management of cancer progression. Joyce and colleagues report that obesity promotes lung neutrophilia in mice, which in the presence of a primary breast tumour fosters metastasis to the lung in a manner dependent on GM-CSF and IL5.

The authors provide preclinical testing of a CSFR-1 inhibitor in proneural glioma models. The compound targets macrophages in the tumor microenvironment rather than tumor cells themselves and is shown to portend considerable antitumor effects. Its activity relies on re-education of tumor-associated macrophages without affecting their survival, reverting their tumor-promoting phenotype. Moreover, gene signatures capturing the tumorigenic features of macrophages can predict survival in human patients with glioma, underscoring the potential relevance of this strategy as a glioma therapy. Glioblastoma multiforme (GBM) comprises several molecular subtypes, including proneural GBM. Most therapeutic approaches targeting glioma cells have failed. An alternative strategy is to target cells in the glioma microenvironment, such as tumor-associated macrophages and microglia (TAMs). Macrophages depend on colony stimulating factor-1 (CSF-1) for differentiation and survival. We used an inhibitor of the CSF-1 receptor (CSF-1R) to target TAMs in a mouse proneural GBM model, which significantly increased survival and regressed established tumors. CSF-1R blockade additionally slowed intracranial growth of patient-derived glioma xenografts. Surprisingly, TAMs were not depleted in treated mice. Instead, glioma-secreted factors, including granulocyte-macrophage CSF (GM-CSF) and interferon-γ (IFN-γ), facilitated TAM survival in the context of CSF-1R inhibition. Expression of alternatively activated M2 markers decreased in surviving TAMs, which is consistent with impaired tumor-promoting functions. These gene signatures were associated with enhanced survival in patients with proneural GBM. Our results identify TAMs as a promising therapeutic target for proneural gliomas and establish the translational potential of CSF-1R inhibition for GBM.

Lung cancer is the leading cause of cancer-related deaths. An enhanced understanding of the immune microenvironments within these tumours may foster more precise and efficient treatment, particularly for immune-targeted therapies. The spatial architectural differences between lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are relatively unexplored. Here, we applied imaging mass cytometry to a balanced cohort of LUAD and LUSC patients, matched for clinical factors such as age, sex, and smoking history, to analyze 204 histopathology images of tumours from 102 individuals with non-small cell lung cancer (NSCLC). By analyzing interactions and broader cellular networks, we interrogate the tumour microenvironment to understand how immune cells are spatially organized in clinically matched adenocarcinoma and squamous cell carcinoma subsets. This spatial analysis revealed distinct patterns of immune cell aggregation, particularly among macrophage populations, that correlated with patient prognosis differentially in adenocarcinoma and squamous cell carcinoma, suggesting potential new strategies for therapeutic intervention. Our findings underscore the importance of analyzing NSCLC histological subtypes separately when investigating the spatial immune landscape, as microenvironmental characteristics and cellular interactions differed by subtype. Recognizing these distinctions is essential for designing precision therapies tailored to each subtype’s unique immune architecture, ultimately enhancing patient outcomes. The spatial architecture of the lung cancer microenvironment could influence the survival outlook and therapeutic options of patients. Here the authors find distinct patterns and composition of immune cells when comparing lung adenocarcinomas and lung squamous cell carcinomas, paving way for precision immune therapy according to histological subtype.

Plasticity of neoplasia, whereby cancer cells attain stem-cell-like properties, is required for disease progression and represents a major therapeutic challenge. We report that in breast cancer cells NANOG , SNAIL and NODAL transcripts manifest multiple isoforms characterized by different 5’ Untranslated Regions (5’UTRs), whereby translation of a subset of these isoforms is stimulated under hypoxia. The accumulation of the corresponding proteins induces plasticity and “fate-switching” toward stem cell-like phenotypes. Mechanistically, we observe that mTOR inhibitors and chemotherapeutics induce translational activation of a subset of NANOG , SNAIL and NODAL mRNA isoforms akin to hypoxia, engendering stem-cell-like phenotypes. These effects are overcome with drugs that antagonize translational reprogramming caused by eIF2α phosphorylation (e.g. ISRIB), suggesting that the Integrated Stress Response drives breast cancer plasticity. Collectively, our findings reveal a mechanism of induction of plasticity of breast cancer cells and provide a molecular basis for therapeutic strategies aimed at overcoming drug resistance and abrogating metastasis. Protein synthesis suppression protects breast cancer cells from clinically relevant stresses like hypoxia. Here, the authors show that unique mRNA isoforms that govern stem cell-like phenotypes escape translational repression to drive tumor progression and chemoresistance.

Visualization of the cellular heterogeneity and spatial architecture of the tumor microenvironment (TME) is becoming increasingly important to understand mechanisms of disease progression and therapeutic response. This is particularly relevant in the era of cancer immunotherapy, in which the contexture of immune cell positioning within the tumor landscape has been proven to affect efficacy. Although single-cell technologies have mostly replaced conventional approaches to analyze specific cellular subsets within tumors, those that integrate a spatial dimension are now on the rise. In this Review, we assess the strengths and limitations of emerging spatial technologies with a focus on their applications in tumor immunology, as well as forthcoming opportunities for artificial intelligence (AI) and the value of integrating multiomics datasets to achieve a holistic picture of the TME. We are in the midst of an explosion of multiomics and spatial data along with constant innovation of the tools used to study these data. In this Review article, as part of our Cancer Immunology and Immunotherapy series, the authors discuss these innovations and their application to study the tumor microenvironment.

Obesity is associated with both increased cancer incidence and progression in multiple tumour types, and is estimated to contribute to up to 20% of cancer-related deaths. These associations are driven, in part, by metabolic and inflammatory changes in adipose tissue that disrupt physiological homeostasis both within local tissues and systemically. However, the mechanisms underlying the obesity–cancer relationship are poorly understood. In this Review, we describe how the adipose tissue microenvironment (ATME) evolves during body-weight gain, and how these changes might influence tumour initiation and progression. We focus on multiple facets of ATME physiology, including inflammation, vascularity and fibrosis, and discuss therapeutic interventions that have the potential to normalize the ATME, which might be translationally relevant for cancer prevention and therapy. Given that the prevalence of obesity is increasing on an international scale, translational research initiatives are urgently needed to provide mechanistic explanations for the obesity–cancer relationship, and how to best identify high-risk individuals without relying on crude measures, such as BMI.

Metastasis is the predominant cause of cancer-related mortality, despite being a highly inefficient process overall. The vasculature is the gatekeeper for tumor cell seeding within the secondary tissue microenvironment-the rate limiting step of the metastatic cascade. Therefore, factors that regulate vascular physiology dramatically influence cancer outcomes. There are a myriad of physiologic circumstances that not only influence the intrinsic capacity of tumor cells to cross the endothelial barrier, but also that regulate vascular inflammation and barrier integrity to enable extravasation into the metastatic niche. These processes are highly dependent on inflammatory cues largely initiated by the innate immune compartment, that are meant to help re-establish tissue homeostasis, but instead become hijacked by cancer cells. Here, we discuss the scientific advances in understanding the interactions between innate immune cells and the endothelium, describe their influence on cancer metastasis, and evaluate potential therapeutic interventions for the alleviation of metastatic disease. By triangulating the relationship between immune cells, endothelial cells, and tumor cells, we will gain greater insight into how to impede the metastatic process by focusing on its most vulnerable phases, thereby reducing metastatic spread and cancer-related mortality.