Author:

Adriana Albini

Abstract

Cancer is increasingly understood not solely as a genetic disease, but as a pathology shaped by its surrounding microenvironment. The tumor microenvironment (TME) is a complex and dynamic ecosystem composed of immune cells, stromal cells, blood vessels, extracellular matrix and signaling molecules that support tumor survival, growth, and resistance to therapy. Central to this environment is the role of innate immune cells, including neutrophils, macrophages, dendritic cells and innate lymphoid cells (ILC), which may be reprogrammed by tumors to promote immune suppression, angiogenesis, and metastasis. Historical insights, from Virchow's inflammation theory to Paget's "seed and soil" hypothesis and Hanahan and Weinberg’s evolving Hallmarks of Cancer, have progressively reframed our understanding of cancer as a disease of both cells and context. By examining the mechanisms through which the TME shapes cancer detection, immune evasion, and therapy resistance, we see the importance of targeting not just tumor cells, but the ecosystem that sustains them.

Introduction

Cancer has long been understood as a disease primarily driven by genetic mutations. For much of the 20th century, pathology examination focused almost exclusively on tumor cells themselves, and most research was devoted to examining how mutations led to uncontrolled proliferation. However, over the past decades, a new perspective has emerged: cancer is not an isolated event within the body but rather a disease that develops in a highly complex ecosystem — the tumor microenvironment (TME). Within this dynamic setting, the innate immune system plays a pivotal role, acting as both a defender against malignancies and, paradoxically, a facilitator of tumor progression.

The recognition that tumors do not exist in isolation but instead communicate with and manipulate their surroundings has fundamentally altered our approach to cancer detection and treatment. The TME, composed of stromal cells, immune cells, blood vessels, extracellular matrix (ECM) and signaling molecules, provides tumors with essential support, allowing them to evade immune attack and resist therapies. The innate immune system, traditionally considered a first line of defense against infections and abnormal cells, is now known to be a key player in the cancer environment. Tumors actively recruit and reprogram immune cells, creating a fostering and immunosuppressive milieu that promotes survival, immune control escape, angiogenesis, and metastasis.

Understanding how tumors interact with their surroundings has led to the development of novel immunotherapies, targeted treatments and biomarker-based diagnostics.

From a Tumor-Centric to a Microenvironment-Centric View of Cancer

Traditionally, cancer was considered an organ-or tissue-autonomous disease, driven by purely internal or external causing agents. After the origins of the cell theory, cancer was defined as a cellular pathology, and in the recent decades its origins were attributed to mutations in oncogenes and tumor suppressor genes. However, several landmark discoveries challenged this paradigm and highlighted the importance of the tumor's surrounding environment.

In 1761, Italian anatomist Giovanni Battista Morgagni laid the foundation for modern pathology by refuting the humoral theory of disease and demonstrating that illnesses originate from structural lesions within specific organs. Around 1800, French anatomist Marie-François-Xavier Bichat expanded this concept by identifying 21 distinct tissue types in the human body. His recognition that diseases could affect individual tissues rather than entire organs was a pivotal step toward understanding the intricate interactions between cells and their surrounding environment.

In the mid-19th century, French physiologist Claude Bernard introduced the concept of internal environment (milieu intérieur), stating that “histological cells are not abandoned naked in the ambient world. They bathe in an internal environment (milieu intérieur) that envelops them, separates them from the outside and serves as an intermediary between them and the cosmic environment .… Thus it is in the milieu intérieur that the physical conditions of life reside (Bernard 1878, p. 4-5).” The physiological and pathological conditions of the cells are therefore directly linked to the microenvironment.

One of the earliest insights into the role of the TME came from German physician, pathologist, and biologist Rudolf Virchow who in 1863 observed that tumors often arise in areas of chronic inflammation, suggesting a link between inflammation and cancer development (Balkwill and Mantovani, 2001). He was also involved in the study of phlebitis (inflammation of a vein) as a cause of many diseases and proposed that masses in blood vessels resulted from “thrombosis”. His observations laid the groundwork for understanding how the microenvironment influences tumor growth.

A pivotal moment in the history of TME research was the proposal of the "seed and soil" hypothesis by the British surgeon and pathologist Stephen Paget in 1889. Studying breast cancer metastases, Paget observed that tumor cells (the "seed") do not randomly spread (Paget, 1889) but rather establish themselves in specific organs ("soil") that provide a favorable microenvironment. This idea was largely overlooked until the 1970s, when the American cancer researcher and tumor biologist Isaiah J. Fidler provided experimental evidence that metastasis is a highly selective process and that tumors actively prepare distant organs for colonization (Fidler, 2003) by secreting signaling molecules that condition the target tissues — a concept now known as the pre-metastatic niche.

Metastasis and angiogenesis research also made its way back to Europe, in part thanks to Raffaella Giavazzi, an Italian student of Fidler. A major research hub on inflammation emerged at the Mario Negri Institute in Milan led by scientists such as Alberto Mantovani, Raffaella Giavazzi and Elisabetta Dejana. Meanwhile, other prominent European researchers, including Fran Balkwill in England, contributed significantly to the field of inflammation and its role in cancer.

In the 1990s and 2000s, a publication which rapidly became a seminal “handbook” was put together by Douglas Hanahan and Robert Weinberg, “The Hallmarks of Cancer Model”, first published in 2000, updated in 2011 and again in 2022. This model evolved from a primarily tumor-centric perspective to a “host” oriented one. This framework introduced angiogenesis, immune evasion and inflammation as critical components of tumor progression, emphasizing that the tumor is deeply integrated with and dependent on its surrounding environment. The TME was no longer considered a passive bystander but rather an active, evolving participant in cancer progression. This paved the way for the development of endothelium and stromal-targeting agents, metabolic therapies and immunotherapies designed to reshape the tumor’s surroundings rather than just targeting cancer cells directly.

The Key Players of the Tumor Microenvironment

The TME is a highly dynamic and complex ecosystem comprising tumor cells, immune cells, blood vessels, fibroblasts, myofibroblasts, signaling molecules, and ECM components. At its core, the TME is driven by the interactions between these diverse elements, which collectively influence cancer progression and therapy response.

Tumor Cells

Tumor cells are the primary players of the TME, continuously evolving to evade immune surveillance and therapeutic interventions. They interact with their surroundings through a network of cytokines, growth factors, and exosomes, which modulate the behavior of stromal and immune cells. This communication network allows tumor cells to manipulate their environment in ways that support their growth and survival. The microenvironment supports tumor heterogeneity in a “spatially” oriented crosstalk.

Stromal Cells and Blood Vessels

Stromal cells, including fibroblasts (Mao et al., 2013) play critical roles in the TME. Fibroblasts can be converted into cancer-associated fibroblasts (CAFs), which actively support (Henke et al., 2020) tumor growth by secreting growth factors and remodeling the extracellular matrix.

Endothelial cells are responsible for angiogenesis, forming new blood vessels (Jain, 2014) or branching from existing ones, that supply oxygen and nutrients essential for tumor expansion. Smooth muscle cells and pericytes, which envelop blood vessels, regulate vascular stability and influence the infiltration of immune cells into the tumor.

Innate Immune Cells in the TME

The innate immune system, including neutrophils, macrophages, dendritic cells, and innate lymphoid cells, in particular natural killer (NK) cells, plays a paradoxical role in cancer. While innate immune cells attack tumor cells as their major role, often they are reprogrammed , or “polarized” to support tumor growth. (Albini et al 2018)

Neutrophils the most abundant Polymorphonuclear cells (PMNs) represent the first line of defence. They exert a remarkable array of cellular functions: chemotaxis and transmigration, adhesion, phagocytosis, degranulation, oxygen radical production.

A major component of innate immunity, they can adopt a tumor-promoting phenotype under certain conditions. Tumors recruit neutrophils through the production of chemokines (Murdoch et al., 2008) to support angiogenesis, remodel the ECM, and facilitate metastasis. Some neutrophils form neutrophil extracellular traps (NETs) which capture circulating tumor cells but may also aid in metastatic dissemination. Targeting these processes offers a potential strategy to reduce metastatic spread.

Macrophages are myeloid cells that play a crucial role in the innate immune system. They possess dual functions: they can directly attack tumor cells and also present antigens acquired from tumors to receptors on lymphocytes, thereby activating adaptive immunity. Initially macrophages were described as existing in two distinct states: M1 (anti-tumor) and M2 (pro-tumor). While M1 macrophages attack tumor cells by releasing pro-inflammatory cytokines and toxic molecules, tumors frequently reprogram macrophages into the M2 phenotype (Locy et al., 2018), which suppresses immune responses, enhances angiogenesis, and promotes metastasis. High levels of M2-like tumor-associated macrophages (TAMs) are associated with poor prognosis in many cancers, prompting investigation into therapeutic strategies aimed at modulating macrophage polarization.

Recently, it has emerged that macrophages in the tumor microenvironment (TME) can exhibit a range of phenotypes that extend beyond the traditional M1 and M2 classification. These cells can display mixed or intermediate phenotypes, influenced by environmental signals within the TME.

Dendritic cells (DCs), other antigen presenting cells (APC) which normally activate T cell responses, often become dysfunctional in the TME. Tumors secrete factors that prevent DCs from presenting antigens effectively. Without proper antigen presentation, adaptive immune responses are weakened, allowing tumors to evade destruction.

Natural killer (NK) cells, a subset of ILC possess sophisticated mechanisms for detecting and eliminating cancer cells. These mechanisms were largely elucidated by Lorenzo and Alessandro Moretta initially in Lausanne and later in Genova, Italy (Moretta 2004). However, NK cells are often rendered ineffective (Gonzalez-Gugel et al., 2016) in the TME. Tumors suppress NK cell activity by downregulating activating receptors and releasing immunosuppressive cytokines such as TGF-β. NK cells can be polarized to a cancer promoting phenotype, becoming decidual-like NK (Albini A and Noonan DM, 2019). Recent advances in CAR-NK cell therapy aim to overcome these barriers, enhancing NK cell-mediated tumor destruction.

Additionally, myeloid-derived suppressor cells (MDSCs) are key players (Guerrouahen et al., 2020) in immune suppression within the TME. These cells inhibit T cell and NK cell function, creating an environment that favors tumor survival. Emerging therapies aim to block MDSC recruitment and reverse their suppressive effects, thereby restoring anti-tumor immunity.

The Extracellular Matrix (ECM)

The extracellular matrix (ECM), composed mostly by collagen fibronectin or laminin and proteoglycans, provides structural support but also modulates tumor behavior, influencing cell adhesion, migration, invasion and survival. Tumor cells actively remodel the ECM (Huang et al., 2021) by producing matrix metalloproteinases (MMPs) and urokinase, which degrade ECM proteins and create pathways for invasion. This process is facilitated by fibroblasts, which can be reprogrammed into cancer-associated fibroblasts (CAFs) that support tumor progression by secreting growth factors, cytokines and proteases.

The ECM also plays a key role in therapy resistance. The dense, fibrotic stroma found in pancreatic and breast tumors (Feng et al., 2024), for instance, impedes drug penetration, making chemotherapy less effective. Emerging therapies aim to modulate ECM stiffness and improve drug delivery by targeting components such as fibronectin, collagen, and laminins.

How the TME Shapes Cancer Detection and Treatment

The growing understanding of the TME has led to major advances in cancer diagnostics and treatment strategies. One of the most crucial developments is the use of liquid biopsies, which detect circulating tumor cells (Bartelink et al., 2019) (CTCs), extracellular vesicles (EVs), and immune markers in blood samples. These approaches provide a minimally invasive way to monitor cancer progression and predict therapy responses.

New therapeutic approaches focus on reprogramming the TME rather than solely targeting tumor cells. The first one of these TME directed therapies was anti-angiogenesis (see the specific chapter)

Targeting hypoxia, a key feature of the TME, is another promising avenue. Tumors often thrive in low-oxygen conditions, activating hypoxia-inducible factors (HIFs) that promote (Dewhirst et al., 2008) the transcription of genes for survival, angiogenesis, and resistance to therapy. Inhibiting HIF-1α or using vascular normalization strategies can improve (Goel et al., 2012) drug delivery and immune infiltration.

Adaptive immunity has been harnessed to combat cancer by removing molecular barriers constructed by cancer cells, which impede checkpoint activity — essentially recognizing an alien and destroying it. Checkpoint blockade inhibitors such as anti-CTLA-4 (ipilimumab) (Longo et al., 2019) and anti-PD-1 (pembrolizumab, nivolumab), were among the first molecules of this class developed and have revolutionized treatment by reawakening immune responses against tumors. However, many patients fail to respond, largely due to an immunosuppressive TME. For instance, a barrier of macrophages can prevent T cells from entering the tumor, inducing a “cold” environment as opposed to a lymphocyte-inflamed one.

Combining checkpoint inhibitors with TME-targeted drugs (Dianat-Moghadam et al., 2023), such as TAM inhibitors (CSF1R blockers), anti-inflammatory, and ECM-modifying agents, may enhance their efficacy.

Tumor microenvironment and inflammation can also be reshaped in a preventive way, with dietary derivatives of repurposed drugs, such as aspirin, and become a target of cancer prevention (Albini A and Sporn M, 2007)

Conclusion

The recognition of the tumor microenvironment’s role and its interaction with tumor cells and with innate immunity has fundamentally transformed oncology. No longer seen as a genetic disease alone, cancer is now recognized as a complex, evolving ecosystem that must be reprogrammed rather than simply destroyed. By modulating immune responses, targeting stromal interactions, curbing polarized innate immunity cells and preventing metastatic niche formation, the next generation of cancer therapies offers (Xiao and Yu, 2021) more effective, durable and personalized treatments.

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