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Crossing the blood–brain barrier is a crucial, rate-limiting step of brain metastasis. Understanding of the mechanisms of cancer cell extravasation from brain microcapillaries is limited as the underlying cellular and molecular processes cannot be adequately investigated using in vitro models and endpoint in vivo experiments. Using ultrastructural and functional imaging, we demonstrate that dynamic changes of activated brain microcapillaries promote the mandatory first steps of brain colonization. Successful extravasation of arrested cancer cells occurred when adjacent capillary endothelial cells (EC) entered into a distinct remodeling process. After extravasation, capillary loops were formed, which was characteristic of aggressive metastatic growth. Upon cancer cell arrest in brain microcapillaries, matrix-metalloprotease 9 (MMP9) was expressed. Inhibition of MMP2/9 and genetic perturbation of MMP9 in cancer cells, but not the host, reduced EC projections, extravasation, and brain metastasis outgrowth. These findings establish an active role of ECs in the process of cancer cell extravasation, facilitated by cross-talk between the two cell types. This extends our understanding of how host cells can contribute to brain metastasis formation and how to prevent it.Significance:Tracking single extravasating cancer cells using multimodal correlative microscopy uncovers a brain seeding mechanism involving endothelial remodeling driven by cancer cell–derived MMP9, which might enable the development of approaches to prevent brain metastasis.See related commentary by McCarty, p. 1167

Supplementary Movie 2 from Phosphorylated Caveolin-1 Regulates Rho/ROCK-Dependent Focal Adhesion Dynamics and Tumor Cell Migration and Invasion

Supplementary Video 4 from Phosphorylated Caveolin-1 Regulates Rho/ROCK-Dependent Focal Adhesion Dynamics and Tumor Cell Migration and Invasion

Supplementary Figure 2 from Phosphorylated Caveolin-1 Regulates Rho/ROCK-Dependent Focal Adhesion Dynamics and Tumor Cell Migration and Invasion

Supplementary Video 1 from Phosphorylated Caveolin-1 Regulates Rho/ROCK-Dependent Focal Adhesion Dynamics and Tumor Cell Migration and Invasion

Supplementary Figure 1 from Phosphorylated Caveolin-1 Regulates Rho/ROCK-Dependent Focal Adhesion Dynamics and Tumor Cell Migration and Invasion

Rho/ROCK signaling and caveolin-1 (Cav1) are implicated in tumor cell migration and metastasis; however, the underlying molecular mechanisms remain poorly defined. Cav1 was found here to be an independent predictor of decreased survival in breast and rectal cancer and significantly associated with the presence of distant metastasis for colon cancer patients. Rho/ROCK signaling promotes tumor cell migration by regulating focal adhesion (FA) dynamics through tyrosine (Y14) phosphorylation of Cav1. Phosphorylated Cav1 is localized to protrusive domains of tumor cells and Cav1 tyrosine phosphorylation is dependent on Src kinase and Rho/ROCK signaling. Increased levels of phosphorylated Cav1 were associated with elevated GTP-RhoA levels in metastatic tumor cells of various tissue origins. Stable expression and knockdown studies of Cav1 in tumor cells showed that phosphorylated Cav1 expression stimulates Rho activation, stabilizes FAK association with FAs, and promotes cell migration and invasion in a ROCK-dependent and Src-dependent manner. Tyrosine-phosphorylated Cav1, therefore, functions as an effector of Rho/ROCK signaling in the regulation of FA turnover and, thereby, tumor cell migration and invasion. These studies define a feedback loop between Rho/ROCK, Src, and phosphorylated Cav1 in tumor cell protrusions, identifying a novel function for Cav1 in tumor metastasis that may contribute to the poor prognosis of some Cav1-expressing tumors. [Cancer Res 2008;68(20):8210–20]

Supplementary Video 3 from Phosphorylated Caveolin-1 Regulates Rho/ROCK-Dependent Focal Adhesion Dynamics and Tumor Cell Migration and Invasion

Supplementary Table 1 from Phosphorylated Caveolin-1 Regulates Rho/ROCK-Dependent Focal Adhesion Dynamics and Tumor Cell Migration and Invasion

Crossing the blood–brain barrier is a crucial, rate-limiting step of brain metastasis. Understanding of the mechanisms of cancer cell extravasation from brain microcapillaries is limited as the underlying cellular and molecular processes cannot be adequately investigated using in vitro models and endpoint in vivo experiments. Using ultrastructural and functional imaging, we demonstrate that dynamic changes of activated brain microcapillaries promote the mandatory first steps of brain colonization. Successful extravasation of arrested cancer cells occurred when adjacent capillary endothelial cells (EC) entered into a distinct remodeling process. After extravasation, capillary loops were formed, which was characteristic of aggressive metastatic growth. Upon cancer cell arrest in brain microcapillaries, matrix-metalloprotease 9 (MMP9) was expressed. Inhibition of MMP2/9 and genetic perturbation of MMP9 in cancer cells, but not the host, reduced EC projections, extravasation, and brain metastasis outgrowth. These findings establish an active role of ECs in the process of cancer cell extravasation, facilitated by cross-talk between the two cell types. This extends our understanding of how host cells can contribute to brain metastasis formation and how to prevent it. Significance: Tracking single extravasating cancer cells using multimodal correlative microscopy uncovers a brain seeding mechanism involving endothelial remodeling driven by cancer cell–derived MMP9, which might enable the development of approaches to prevent brain metastasis. See related commentary by McCarty, p. 1167

Despite abundant evidence demonstrating that platelets foster metastasis, a therapeutic approach based on anti-platelet agents is not an option due to the risk of hemorrhages. In addition, whether platelets can regulate metastasis at the late stages of the disease remains unknown. In this study, we subjected syngeneic models of metastasis to various thrombocytopenic regimes to show that platelets provide a biphasic contribution to metastasis. While potent intravascular binding of platelets to tumor cells efficiently promotes metastasis, platelets further support the outgrowth of established metastases. Genetic depletion and pharmacological targeting of the platelet-specific receptor GPVI in humanized mouse models efficiently reduced the growth of established metastases, independently of active platelet binding to tumor cells in the bloodstream. Our study is the first to demonstrate therapeutic efficacy when targeting animals carrying growing metastases. It further identifies GPVI as the first molecular target whose inhibition can impair metastasis without inducing collateral hemostatic perturbations.

Metastatic dissemination accounts for most of the death in patients during cancer progression. There is thus an urge to identify specific biomarkers as proxies for cancer progression and assessment of treatment efficiency. Cancer is a systemic disease involving the shuttling of tumor cells and tumor secreted factors to distant organs, mostly via biofluids. During this transfer, these factors are accessible for easy sampling and therefore constitute a unique source of information witnessing the presence and the evolution of the disease. Hence, liquid biopsies offer multiple advantages, including simple and low-invasive sampling procedures, low cost, and higher compliance. Importantly, liquid biopsies are adapted to personalized medicine allowing a longitudinal follow-up to monitor treatment efficiency or resistance, and risk of relapse.The evolution of methodologies to isolate circulating tumor cells (CTCs) and extracellular vesicles (EVs) from blood samples associated with the characterization of their membrane surface repertoire and content have been instrumental in the emergence of liquid biopsies as an easy and non-invasive alternative as opposed to classical surgery-mediated tumor biopsies.In this chapter, we comment on CTCs and EVs carrying features with great potential as cancer biomarkers. More specifically, we focus on the adhesive and mechanical properties of CTCs as metastatic markers. We also consider the recent development of EVs isolation methods and the identification of new biomarkers. Finally, we discuss their relevance as cancer prognosis tools.

The most dangerous aspect of cancer lies in metastatic progression. Tumor cells will successfully form life-threatening metastases when they undergo sequential steps along a journey from the primary tumor to distant organs. From a biomechanics standpoint, growth, invasion, intravasation, circulation, arrest/adhesion, and extravasation of tumor cells demand particular cell-mechanical properties in order to survive and complete the metastatic cascade. With metastatic cells usually being softer than their non-malignant counterparts, high deformability for both the cell and its nucleus is thought to offer a significant advantage for metastatic potential. However, it is still unclear whether there is a finely tuned but fixed mechanical state that accommodates all mechanical features required for survival throughout the cascade or whether tumor cells need to dynamically refine their properties and intracellular components at each new step encountered. Here, we review the various mechanical requirements successful cancer cells might need to fulfill along their journey and speculate on the possibility that they dynamically adapt their properties accordingly. The mechanical signature of a successful cancer cell might actually be its ability to adapt to the successive microenvironmental constraints along the different steps of the journey.

Imaging has had a profound impact on our ability to understand and treat cancer. We invited some experts to discuss imaging approaches that can be used in various aspects of cancer research, from investigating the complexity and diversity of cancer cells and their environments to guiding clinical decision-making.

The intravascular behavior of tumor-derived extracellular vesicles (EVs) and circulating tumor cells (CTCs) lies at the heart of the metastatic cascade. Their capacity to disseminate and stop at specific vascular regions precedes and determines the formation of metastatic foci. We discuss in detail the central role of cellular adhesion molecules (CAMs) that are present on EV/CTC surface, as well as their endothelial ligands, in dictating their arrest site and their capacity to exit the vasculature. We focus on the differences and similarities between CAMs on CTCs and EVs, and speculate about their role in the organotropism of different cancer types. Better understanding of the binding mechanisms might pinpoint potential targets for novel therapies.

Extracellular vesicles (EVs) are lipid-based nano-sized particles that convey biological material from donor to recipient cells. They play key roles in tumour progression, notably in glioblastoma in which the subpopulation of Glioblastoma Stem-like Cells (GSCs) might represent a meaningful source of tumour-derived EVs. However, the mechanisms involved in the production and release of EVs by GSCs are still poorly understood. Here, we report the identification of MLKL, a crucial effector of cell death by necroptosis, as a regulator of the constitutive secretion of small EVs from GSCs. The targeting of MLKL by genetic, protein depletion or chemical approaches alters endosomal trafficking and EV release and reduces GSC expansion in vitro. This function ascribed to MLKL appears independent of its role during necroptosis. In vivo, pharmacological inhibition of MLKL triggers a reduction of both the tumour burden in xenografted mice and of the level of plasmatic EVs. This work reinforces the idea of a non-deadly role for MLKL in endosomal trafficking and suggests that interfering with EV biogenesis is a promising therapeutic option to sensitize glioblastoma cells to death.

Metastatic progression, which begins with the invasion and migration of tumor cells from a primary tumor, marks a major turning point in the evolution of cancer. Indeed, it eventually leads to the formation of secondary tumors, the metastases, which are very often responsible for the patient's death. Understanding the mechanisms controlling the different steps of this process, as well as those explaining the fundamental phenomenon of organotropism (i.e. the distribution of metastases in distant organs by a non-random and tumor-specific process), is essential to define new innovative therapeutic solutions. In this review paper, we will present how biomechanics is an essential element to this understanding, and will emphasize the importance of this orthogonal and promising angle of study as well as our laboratory's focus on the late stages of dissemination, arrest and extravasation of circulating cancer cells and factors secreted by the primary tumor such as extracellular vesicles.La progression métastatique, qui débute par l’invasion et la migration de cellules tumorales depuis une tumeur primaire, marque un tournant majeur dans l’évolution du cancer. En effet, elle conduit à terme à la formation des tumeurs secondaires, les métastases, responsables très souvent de la mort du patient. Comprendre les mécanismes contrôlant les différentes étapes de ce processus, ainsi que ceux expliquant le phénomène fondamental d’organotropisme (c’est-à-dire la distribution des métastases dans les organes distants par un processus non aléatoire et tumeur-spécifique), est essentiel pour définir de nouvelles solutions thérapeutiques innovantes. Dans ce document de synthèse, nous présenterons comment la biomécanique est un élément essentiel à cette compréhension, et insisterons sur l’importance de cet angle d’étude orthogonal et prometteur ainsi que la focalisation de notre laboratoire sur les étapes tardives de dissémination, d’arrêt et d’extravasation des cellules cancéreuses circulantes et des facteurs sécrétés par la tumeur primaire comme les vésicules extracellulaires.

International audience; Among a plethora of functions, extracellular vesicles released by primary tumors spread in the organism and reach distant organs where they can induce the formation of a premetastatic niche. This constitutes a favorable microenvironment for circulating tumor cells which facilitates their seeding and colonization. In this review, we describe the journey of extracellular vesicles (EVs) from the primary tumor to the future metastatic organ, with a focus on the mechanisms used by EVs to target organs with a specific tropism (i.e., organotropism). We then highlight important tumor EV cargos in the context of premetastatic niche formation and summarize their known effects on extracellular matrix remodeling, angiogenesis, vessel permeabilization, resident cell activation, recruitment of foreign cells, and ultimately the formation of a pro-inflammatory and immuno-tolerant microenvironment. Finally, we discuss current experimental limitations and remaining opened questions in light of metastatic diagnosis and potential therapies targeting PMN formation.

International audience; Endothelial senescence has been identified as an early event in the development of endothelial dysfunction, a hallmark of cardiovascular disease. This study developed theranostic nanocarriers (NC) decorated with VCAM-1 antibodies (NC-VCAM-1) in order to target cell surface VCAM-1, which is overexpressed in senescent endothelial cells (ECs) for diagnostic and therapeutic purposes. Incubation of Ang IIinduced premature senescent ECs or replicative senescent ECs with NC-VCAM-1 loaded with lipophilic fluorescent dyes showed higher fluorescence signals than healthy EC, which was dependent on the NC size and VCAM-1 antibodies concentration, and not observed following masking of VCAM-1. NC loaded with omega 3 polyunsaturated fatty acid (NC-EPA:DHA6:1) were more effective than native EPA:DHA 6:1 to prevent Ang II-induced VCAM-1 and p53 upregulation, and SA-β-galactosidase activity in coronary artery segments. These theranostic NC might be of interest to evaluate the extent and localization of endothelial senescence and to prevent pro-senescent endothelial responses.

Established protocols for correlating intravital microscopy with electron microscopy remain cumbersome and mostly rely on a combination of artificial fiducials with anatomical landmarks. A recent study describes a new workflow, achieving label-free 3D correlative light and electron microscopy in the mouse brain.

Cancer metastasis is a multistep process during which tumor cells leave the primary tumor mass and form distant secondary colonies that are lethal. Circulating tumor cells (CTCs) are transported by body fluids to reach distant organs, where they will extravasate and either remain dormant or form new tumor foci. Development of methods to study the behavior of CTCs at the late stages of the intravascular journey is thus required to dissect the molecular mechanisms at play. Using recently developed microfluidics approaches, we have demonstrated that CTCs arrest intravascularly, through a two-step process: (a) CTCs stop using low energy and rapidly activated adhesion receptors to form transient metastable adhesions and (b) CTCs stabilize their adhesions to the endothelial layer with high energy and slowly activated adhesion receptors. In this methods chapter, we describe these easy-to-implement quantitative methods using commercially available microfluidic channels. We detail the use of fast live imaging combined to fine-tuned perfusion to measure the adhesion potential of CTC depending on flow velocities. We document how rapidly engaged early metastable adhesion can be discriminated from slower activated stable adhesion using microfluidics. Finally, CTC extravasation potential can be assessed within this setup using long-term cell culture under flow. Altogether, this experimental pipeline can be adapted to probe the adhesion (to the endothelial layer) and extravasation potential of any circulating cell.

Formerly considered as insignificant cell debris, extracellular vesicles (EVs) have emerged as potent mediators of cell-cell communication, both in proximity and at distance from the producing cell. EVs are transported in body fluids and can be internalized by specific distant cells to ultimately deliver a functional message. Despite their striking importance in many physiological and pathological contexts, the exact mechanisms by which EVs impose local and distant modifications of the microenvironment in vivo remain to be fully understood. We realized that some conceptual gaps are direct consequences of the difficulty to visualize the shuttling and targeting of EVs in real time in vivo. The zebrafish larvae offered attractive features for live tracking of EVs, within circulating fluids. Here, we describe the experimental procedures that we have built for dissecting the dissemination of EVs at high spatio-temporal resolution in vivo.

International audience; Cancer is a multi-step disease where an initial tumour progresses through critical steps shaping, in most cases, life-threatening secondary foci called metastases. The oncogenic cascade involves genetic, epigenetic, signalling pathways, intracellular trafficking and/or metabolic alterations within cancer cells. In addition, pre-malignant and malignant cells orchestrate complex and dynamic interactions with non-malignant cells and acellular matricial components or secreted factors within the tumour microenvironment that is instrumental in the progression of the disease. As our aptitude to effectively treat cancer mostly depends on our ability to decipher, properly diagnose and impede cancer progression and metastasis formation, full characterisation of molecular complexes and cellular processes at play along the metastasis cascade is crucial. For many years, the scientific community lacked adapted imaging and molecular technologies to accurately dissect, at the highest resolution possible, tumour and stromal cells behaviour within their natural microenvironment. In that context, the NANOTUMOR consortium is a French national multi-disciplinary workforce which aims at a providing a multi-scale characterisation of the oncogenic cascade, from the atomic level to the dynamic organisation of the cell in response to genetic mutations, environmental changes or epigenetic modifications. Ultimately, this program aims at identifying new therapeutic targets using innovative drug design.

Description, Intravital imaging guides a personalized medicine approach to target mechanoreciprocity in pancreatic cancer., Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic, chemoresistant malignancy and is characterized by a dense, desmoplastic stroma that modulates PDAC progression. Here, we visualized transient manipulation of focal adhesion kinase (FAK), which integrates bidirectional cell-environment signaling, using intravital fluorescence lifetime imaging microscopy of the FAK-based Förster resonance energy transfer biosensor in mouse and patient-derived PDAC models. Parallel real-time quantification of the FUCCI cell cycle reporter guided us to improve PDAC response to standard-of-care chemotherapy at primary and secondary sites. Critically, micropatterned pillar plates and stiffness-tunable matrices were used to pinpoint the contribution of environmental cues to chemosensitization, while fluid flow–induced shear stress assessment, patient-derived matrices, and personalized in vivo models allowed us to deconstruct how FAK inhibition can reduce PDAC spread. Last, stratification of PDAC patient samples via Merlin status revealed a patient subset with poor prognosis that are likely to respond to FAK priming before chemotherapy.

International audience

International audience; Cancer extracellular vesicles (EVs) shuttle at distance and fertilize pre-metastatic niches facilitating subsequent seeding by tumor cells. However, the link between EV secretion mechanisms and their capacity to form pre-metastatic niches remains obscure. Using mouse models, we show that GTPases of the Ral family control, through the phospholipase D1, multi-vesicular bodies homeostasis and tune the biogenesis and secretion of pro-metastatic EVs. Importantly, EVs from RalA or RalB depleted cells have limited organotropic capacities in vivo and are less efficient in promoting metastasis. RalA and RalB reduce the EV levels of the adhesion molecule MCAM/CD146, which favors EV-mediated metastasis by allowing EVs targeting to the lungs. Finally, RalA, RalB and MCAM/CD146, are factors of poor prognosis in breast cancer patients. Altogether, our study identifies RalGTPases as central molecules linking the mechanisms of EVs secretion and cargo loading to their capacity to disseminate and induce pre-metastatic niches in a CD146 dependent manner.

International audience; Cancer extracellular vesicles (EVs) mainly exert pro-tumoral functions by changing the phenotypes of stromal cells to the benefit of tumor growth and metastasis. They shuttle to distant organs and fertilize pre-metastatic niches facilitating subsequent seeding by circulating tumor cells. The levels of tumor secreted EVs correlate with tumor aggressiveness, however, the link between EV secretion mechanisms and their capacity to form pre-metastatic niches remains obscure. Here, we show that GTPases of the Ral family control, through the phospholipase D1, multi-vesicular bodies homeostasis and thereby tune the biogenesis and secretion of pro-metastatic EVs. RalA and RalB promote lung metastasis in a syngeneic mouse model. Importantly, EVs from RalA or RalB depleted cells have limited organotropic capacities in vivo and, as a consequence, are less efficient in promoting lung metastasis. RalA or RalB modulate the EV levels of the adhesion molecule MCAM/CD146, which mediates lung col-onization. Finally, RalA and RalB, but also MCAM/CD146, are factors of poor prognosis in human breast cancer patients. Altogether , our study identifies Ral GTPases as central molecules linking the mechanisms of EVs secretion, cargo loading to their capacity to disseminate and induce pre-metastatic niches.

Clustering of tumor cells is known to grant superior metastatic efficiency compared with single cells. However, the mechanisms involved remain elusive. Reporting in Cell, Wrenn et al. describe how sealed intercellular compartments, nanolumina, are used as growth factor reservoirs within tumor cell clusters to regulate tumor cell proliferation.

Metastases are the main cause of cancer-related deaths. The chain of events leading to their development is called "the metastatic cascade". The biological and biochemical aspects of this process have been well studied but the importance of biomechanical parameters only recently became a focus in the field. Studies have shown the biological fluids (blood, lymph and interstitial fluid) to play a key role in the metastatic cascade. These fluids participate in the transport of circulating tumor cells (CTCs) as well as the factors that they secrete, while at the same time influencing the events of the metastatic cascade through the forces that they generate. The hemodynamic properties and topological constraints of the vascular architecture control the formation of metastatic niches and the metastatic potential of tumor cells. In this review, we discuss the importance of these mechanical forces and highlight the novel questions and research avenues that they open.Influence de la mécanique des fluides sur la formation des métastases.La suite d’évènements menant à l’apparition de métastases est appelée « cascade métastatique ». L’étude récente de la composante biomécanique de cette cascade a révélé le rôle central des liquides biologiques dans la dissémination métastatique. Tout en participant au transport des cellules tumorales circulantes et des facteurs qu’elles sécrètent, ces liquides circulants influencent cette cascade par les forces mécaniques qu’ils génèrent. Les propriétés hémodynamiques et les contraintes topologiques de l’architecture vasculaire contrôlent la formation de niches métastatiques et le potentiel métastatique des cellules tumorales.

Dissemination and replication of viruses into hosts is a multistep process where viral particles infect, navigate, and indoctrinate various cell types. Viruses can reach tissues that are distant from their infection site by subverting subcellular mechanisms in ways that are, sometimes, disruptive. Modeling these steps, at appropriate resolution and within animal models, is cumbersome. Yet, mimicking these strategies in vitro fails to recapitulate the complexity of the cellular ecosystem. Here, we will discuss relevant in vivo platforms to dissect the cellular and molecular programs governing viral dissemination and briefly discuss organoid and ex vivo alternatives. We will focus on the zebrafish model and will describe how it provides a transparent window to unravel new cellular mechanisms of viral dissemination in vivo., Highlights The zebrafish model allows in vivo investigations of virus-induced molecular processes at subcellular resolution. Viruses have evolved multiple strategies for disseminating over long distance, including by indoctrinating host cell types with high migration potential. Organoids derived from stem cells emerge as powerful alternatives to unravel new molecular mechanisms of viral dissemination.

International audience; La suite d’évènements menant à l’apparition de métastases est appelée « cascade métastatique ». L’étude récente de la composante biomécanique de cette cascade a révélé le rôle central des liquides biologiques dans la dissémination métastatique. Tout en participant au transport des cellules tumorales circulantes et des facteurs qu’elles sécrètent, ces liquides circulants influencent cette cascade par les forces mécaniques qu’ils génèrent. Les propriétés hémodynamiques et les contraintes topologiques de l’architecture vasculaire contrôlent la formation de niches métastatiques et le potentiel métastatique des cellules tumorales.

Tumor progression and metastatic dissemination are driven by cell-intrinsic and biomechanical cues that favor the growth of life-threatening secondary tumors. We recently identified prometastatic vascular regions with blood flow profiles that are permissive for the arrest of circulating tumor cells. We have further established that such flow profiles also control endothelial remodeling, which favors extravasation of arrested CTCs. Yet, how shear forces control endothelial remodeling is unknown. In the present work, we aimed at dissecting the cellular and molecular mechanisms driving blood flow-dependent endothelial remodeling. Transcriptomic analysis revealed that blood flow modulated several signaling pathways in endothelial cells. More specifically, we observed that VEGFR signaling was significantly enhanced. Using a combination of in vitro microfluidics and intravital imaging in zebrafish embryos, we now demonstrate that the early flow-driven endothelial response can be prevented with sunitinib, a pan-inhibitor of VEGFR signaling. Embryos treated with sunitinib displayed reduced endothelial remodeling and subsequent metastatic extravasation. These results confirm the importance of endothelial remodeling as a driving force of CTC extravasation and metastatic dissemination. Furthermore, the present work suggests that therapies targeting endothelial remodeling might be a relevant clinical strategy in order to impede metastatic progression.Highlights-Flow profiles that are permissive for metastasis stimulate the VEGFR pathway-Flow-dependent VEGFR signaling favors extravasation of CTCs through endothelial remodeling-Inhibition of VEGFR signaling suppresses early flow-driven endothelial response

International audience

International audience; Considerable progress has been made in the development and understanding of immunotherapy, notably with the emergence of novel chimeric antigen receptor T cells (CAR‐T) which changed the perception of personalized therapy. However, cell‐based immunotherapy not only lacks therapeutic efficiency in various solid cancers but also raises concerns related to important side effects. The convergence of immunotherapy and nanomedicine is timely as nanoparticles can now be easily conjugated to various antibodies and peptides enabling outstanding abilities to target specific cell populations in vivo. Here, the state of the art of immunonanotherapy that activates the immune system in vivo, by acting either as vaccines or as tumor microenvironment (TME) activators is described. Then, the development of ex vivo immune‐cell surface labeling strategies is discussed to exploit immune cells as trojan horses and thereby improving the delivery of the therapeutics in the TME. Such a strategy is likely to considerably amplify the efficacy of immunotherapy.