Tumor-infiltrating B cells complement T cell-mediated antitumor immunity. A panel of experts share their views on the complexity of B cells within the tumor microenvironment, the variety of mechanisms by which these cells control tumor growth, their organization in tertiary lymphoid structures, and their association with immunotherapy response.

Functionally significant proteins expressed by tumor macrophages have emerged as promising anti-cancer targets. In this issue of Cancer Cell, Sun et al. identify two FDA-approved agents that together safely reprogram tumor macrophages into potent anti-tumor effectors, demonstrating the power of engaging both immune system arms to fight cancer.

Overcoming resistance to CDK4/6 inhibitors is a major clinical challenge. In this issue of Cancer Cell, Freeman-Cook et al. study mechanisms of resistance to CDK4/6 inhibitors by employing a CRISPRa screen. They identify the cyclin E-CDK2 axis and Myc signaling as key pathways of resistance and develop PF-06873600, a selective CDK2/4/6 inhibitor.

Diffuse large B cell lymphoma (DLBCL) is a markedly phenotypically heterogenous disease, frequently assessed using bulk genomic techniques that blur the intrinsic heterogeneity of each tumor. In this issue of Cancer Cell, Steen et al. have utilized a computational framework called EcoTyper to skillfully dissect bulk transcriptomic tumor profiles into different cell type components in an unsupervised

The precise role of intestinal ILC3s in cancer remains largely unknown. Published in Cell, Goc et al. describe ILC3 function and plasticity in tumors. ILC3s may lose their identity and thus become either ILC1s or exhausting-ILC3s, which could in turn reshape the gut microbiome for colorectal cancer progression and immunotherapy resistance.

Cancer treatment effectiveness could be improved if it were possible to accurately anticipate the response of the tumor to treatment. Writing in Nature, Salehi et al. combine single-cell genomics and mathematical modeling to measure cancer subclone fitness and use these measurements to accurately predict the future trajectory of cancer evolution.

A recent report in Nature Medicine pinpoints a role for gut microbiota in response and toxicity to combined immune checkpoint blockade targeting CTLA-4 and PD-1. This emergent study provides insights that can be used to leverage microbiota in the design of anticancer therapies to mitigate toxicity while enhancing efficacy.

The human microbiome constitutes a complex multikingdom community that symbiotically interacts with the host across multiple body sites. Host-microbiome interactions impact multiple physiological processes and a variety of multifactorial disease conditions. In the past decade, microbiome communities have been suggested to influence the development, progression, metastasis formation, and treatment response

In this issue of Cancer Cell, Shiao et al. reveal the counteracting role of bacteria and fungi in antitumoral immune responses to radiation therapy (RT). While bacterial depletion impairs the response, fungal depletion improves efficacy of RT. An interplay between innate and adaptive immunity is implicated and orchestrated by Dectin-1.

Fibroblasts are a major non-neoplastic component of solid tumors, yet it is unclear whether they promote or oppose cancer. In this issue of Cancer Cell, Hutton et al. report two distinct fibroblast subpopulations that are defined by a single marker, one subpopulation that is tumor permissive and the other that is tumor suppressive and supports anti-tumor immunity.

The randomized ARTEMIS study demonstrates that adding the VEGF inhibitor bevacizumab to the EGFR inhibitor erlotinib improves progression-free survival in EGFR mutant non-small-cell lung cancer by more than 6 months, with even greater benefits seen in patients with brain metastases and EGFR L858R mutation. This provides further evidence for the tailored use of VEGF/EGFR combinations.

Discrete tissue niches are emerging as essential prerequisites enabling cell communication and function in both homeostasis and disease. In a recent Cell paper, Di Pilato et al. identify a unique dendritic cell-cytotoxic T cell crosstalk within the perivascular space that facilitates T cell survival and proliferation and drives anti-tumor activity.

Cyclin-dependent kinase 7 (CDK7) is implicated in regulating the expression of cancer-dependent genes, and multiple CDK7-targeted therapies are currently under clinical investigation. Three recent studies elucidate the structure of human transcription machinery, offering vital mechanistic insights into CDK7 function and a potential pharmacodynamic marker of CDK7 activity in tumors.

Despite the demonstrated efficacy and broad applicability of checkpoint blockade, the mechanisms by which it exerts its antitumor effects are incompletely understood. A recent article in Nature Medicine describes an ex vivo platform for assessing early responses to checkpoint blockade and the properties of tumor immune contexture in correlation to clinical responses.

Tumor organoids have been proposed as a model system for precision medicine. The ability of tumor organoids to retain characteristics of the original tumor makes them unique for cancer research on an individual patient level. Hence, the idea to use tumor organoids for clinical decision making and optimize patient outcome is tempting. In vitro responses of tumor organoids to a wide array of drugs have

Tumor heterogeneity was traditionally considered in the genetic terms, but it has now been broadened into many more facets. These facets represent a challenge in our understanding of cancer etiology but also provide opportunity for us to understand prognosis and therapy response.

Owing to clinical success of immune-checkpoint blockade, immunotherapy is becoming a cornerstone of modern oncology, and immuno-oncology is at the forefront of basic cancer research. This commentary outlines future opportunities for immuno-oncology modeling.

SARS-CoV-2 vaccines are effective in preventing COVID-19. Patients with cancer are at high risk for severe COVID-19 and are appropriately prioritized for vaccination. Several studies in this issue of Cancer Cell add to our knowledge of the heterogeneity of immune responses to vaccination among patients with cancer and identify important areas for future research.

Resistance to targeted therapies is a major challenge in cancer care and occurs via genetic and non-genetic mechanisms. In this issue of Cancer Cell, Marin-Bejar et al. demonstrate that melanomas recurrently select genetic or non-genetic resistance trajectories and that targeting neural crest stem cell-like cells prevents non-genetic, but not genetic, resistance.

Combining single-cell lineage tracing with RNA sequencing has provided unprecedented opportunities to prospectively explore metastatic dynamics in vivo. In this issue of Cancer Cell, Simeonov et al. developed the macsGESTALT lineage recording system to reveal that hybrid EMT states and S100 expression are associated with elevated metastatic abilities in a pancreatic cancer model.

Recently published in Science, AstroPath outlines a standardized workflow for multiplex immunofluorescence (mIF) panel development, imaging, and analysis; showcases its potential in biomarker discovery for predicting response to anti–PD-1 treatment; and paves the way for large-scale computational pathology studies on high-quality mIF datasets using data-driven machine-learning techniques.

In a recent issue of Nature, Pan and colleagues explore whether light-induced stimulation of the optic nerve could influence the biology of optic gliomas. This study highlights the importance of neuronal-glioma interactions.

RAS mutant tumors have been largely refractory to therapies until now. Recent findings published in the New England Journal of Medicine show that sotorasib provides clinical benefit for KRAS p.G12C-mutated non-small-cell lung cancer (NSCLC) and provide mechanistic insights into acquired resistance to KRASG12C-specific inhibition.

Single-cell technologies are emerging as powerful tools for cancer research. These technologies characterize the molecular state of each cell within a tumor, enabling new exploration of tumor heterogeneity, microenvironment cell-type composition, and cell state transitions that affect therapeutic response, particularly in the context of immunotherapy. Analyzing clinical samples has great promise for

CAR T cell therapy successes are challenged by several mechanisms of resistance including the development of dysfunctional states such as exhaustion. The features of CAR T cell exhaustion, its role in limiting the efficacy of CAR T therapy in both liquid and solid malignancies, and potential strategies to overcome it are discussed.

Precisely how macrophages regulate response to immunotherapy remains unclear. In this issue of Cancer Cell, Chow et al. demonstrate a tumor-promoting role of TIM-4+ cavity macrophages which affects the response of metastatic malignancies to immunotherapy. Specifically, TIM-4+ macrophages engage with phosphatidylserine-expressing cytotoxic T lymphocytes, inhibiting their activity even during PD-1 blockade

I-SPY2 platform-based phase II studies in breast cancer might speed up the development of new treatments. In this issue of Cancer Cell, Pusztai et al. report that adding durvalumab and olaparib to standard neoadjuvant chemotherapy significantly increases the pathological complete response rate in patients with HER2-negative breast cancer irrespective of the hormone receptor status.

Relapse of AML patients to FLT3i treatment is the result of a long-term and stepwise process leading to resistance, whereby residual cancer cells initially survive and subsequently expand. Here, Joshi et al. use a multifaceted approach to characterize how microenvironment-driven early resistance to gilteritinib evolves into mutation-driven late resistance.

Tumor cells undergo rapid aerobic glycolysis to fuel growth and proliferation. A recent finding in Nature reveals that tumor-infiltrating myeloid cells demonstrate greater capacity for glucose uptake than tumor cells and consume significant amounts within the tumor milieu. Unexpectedly, tumor cells account for the highest glutamine utilization in the tumor microenvironment.

A recent article in Nature Medicine explored the combination of immunotherapy with multiple distinct targeted therapies in patients with metastatic urothelial cancer, employing a biomarker-driven approach. Herein, we discuss the merits of this ambitious study and highlight the need for larger biomarker-based randomized trials to arrive at definitive clinical conclusions.

Three articles in Nature show that intestinal stem cells with cancer-promoting mutations could shape the surrounding normal tissue in their favor to promote clonal fixation and field expansion, raising the possibility of developing therapeutic strategies that maintain or enhance the health of normal cells to out-compete the mutant cells.