Cancer remains one of the most significant health challenges humanity faces, and its complexity and persistence compel researchers to explore new perspectives to understand and combat this disease. In recent years, the tumor microenvironment (TME) has emerged as a hotspot in cancer research, revealing new dimensions of cancer development. This article delves into the characteristics, composition, and role of the tumor immune microenvironment, and introduces the five main research directions in current tumor microenvironment studies.

1. History of Cancer Development

The history of cancer research extends back a long way, but key breakthroughs in modern cancer biology began in the 1970s. About 40 years ago, Peter Nowell proposed a groundbreaking idea: genetic alterations might be the fundamental cause of the transformation of normal cells into tumor cells. This theory laid the foundation for "cancer genetics," revealing that cancer is not only influenced by external factors but is primarily caused by genomic instability within cells.

Nowell’s theory highlighted that genetic instability is a hallmark of cancer cells. Over time, tumor cells accumulate numerous genetic mutations, which ultimately lead to malignant transformation. This perspective guided subsequent cancer research and spurred in-depth studies of the cancer genome.

In 2011, Hanahan and Weinberg summarized the main characteristics of cancer cells in their seminal review, enhancing our understanding of cancer's nature. They emphasized that tumor cell growth depends not only on genetic mutations but also on interactions with surrounding cells. Tumor cells can promote angiogenesis, induce inflammatory responses, and develop mechanisms to evade the immune system. Although these functions are driven by genetic mutations, the true aggressiveness of tumor cells is influenced by the selective pressures exerted by the harsh environment.

2. Tumor Immune Microenvironment

As our understanding of cancer has deepened, researchers have come to realize that focusing solely on tumor cells is insufficient. The environment in which tumor cells survive and grow, the tumor microenvironment, plays a crucial role in cancer progression.

2.1 Characteristics of the Tumor Microenvironment

The tumor microenvironment is an extremely complex ecosystem with several key characteristics:

1) Hypoxic Environment: Due to rapid tumor growth and an inadequate blood supply, tumors often experience oxygen shortages. This hypoxic environment forces tumor cells to adapt and develop new survival strategies.

2) Acidic Environment: Hypoxia leads to tumor cells primarily relying on anaerobic glycolysis for energy production, resulting in high lactate production. Additionally, ion exchange proteins on the tumor cell membrane continuously transport H+ ions out of the cell, contributing to the acidic nature of the tumor microenvironment.

3) Inflammatory Environment: During tumor development, hypoxia and acidity cause extensive cell death, releasing cellular debris and chemokines, which trigger inflammatory cell infiltration and the release of inflammatory factors. Tumors also induce immune system responses, further exacerbating local inflammation.

2.2 Role of the Tumor Microenvironment

Despite its seemingly harsh nature, the tumor microenvironment promotes tumor initiation and progression. The relationship between tumors and their microenvironment is often compared to "seed and soil." Tumor cells release various signaling molecules to influence the surrounding environment, promoting angiogenesis and inducing immune tolerance, while cells in the microenvironment, particularly immune cells, affect tumor cell growth and development.

2.3 Major Immune Cells in the Tumor Microenvironment

Figure 1. The Tumor Microenvironment and Immune Contexture in Cancer. (Giraldo NA, et al., 2019)

The tumor microenvironment contains various immune cells that play complex and crucial roles in tumor progression:

1) Tumor-Associated Macrophages (TAMs): TAMs are among the most abundant immune cells in the tumor microenvironment. They can be classified into M1 and M2 subtypes, with M1 exhibiting anti-tumor effects and M2 promoting tumor growth and metastasis. The plasticity of TAMs makes them an important target for immunotherapy.

2) NK Cells: As a key component of the innate immune system, NK cells can recognize and kill tumor cells with downregulated MHC-I expression, playing a significant role in anti-tumor immunity.

3) Dendritic Cells (DCs): DCs bridge innate and adaptive immune responses. In the tumor microenvironment, DCs often display immature and inhibitory phenotypes, affecting their ability to activate T cells.

4) CD4+ T and CD8+ T Cells: These T cells play essential roles in anti-tumor immunity. CD4+ T helper cells can be further divided into subtypes, with Th1 responses typically associated with better prognosis. CD8+ T cells directly recognize and kill tumor cells.

5) B Lymphocytes: B cells enhance T cell responses through antibody production, cytokine, and chemokine secretion, and may also exert immunoregulatory effects through factors like IL-10.

2.4 Tertiary Lymphoid Structures (TLS)

Tertiary lymphoid structures are specialized immune cell aggregates found in the tumor microenvironment. TLS is typically located at the tumor's invasive margins or stroma and resembles secondary lymphoid organs, containing T cell zones, B cell follicles, and high endothelial venules. The presence of TLS is believed to reflect ongoing immune responses within the tumor and may play a crucial role in initiating and maintaining local anti-tumor immunity.

2.5 Spatiotemporal Dynamics of the Tumor Immune Microenvironment

The tumor microenvironment is a dynamic system. Chemokines ensure the local migration of different cell types, while cytokines facilitate their interactions. As tumors progress, the composition of immune cells in the microenvironment changes. For example, in colorectal cancer, the density of B cells and myeloid cells increases with the tumor stage. These dynamic changes create a specific "immune landscape" during tumor progression.

If you're researching the tumor microenvironment, Creative Biogene offers a variety of high-quality tools to advance your work. Our product lineup includes:

Premade Virus Particles: Ideal for manipulating gene expression related to the tumor microenvironment.

Clones: Achieve stable gene expression in the tumor microenvironment for reliable research results.

Transfected Stable Cell Lines: Study gene functions and interactions within the tumor microenvironment.

Protease/Phosphatase Assay Kits: Detect enzyme activity related to cancer progression.

LPS Extraction Kit: Study the relationship between inflammation and tumor progression.

Below is a list of partial related products:

3. Five Main Directions in Tumor Microenvironment Research

Based on the complexity of the tumor microenvironment, current research focuses on the following five directions:

3.1 Tumor Immunity

Research primarily focuses on the mechanisms of interaction between tumor cells and TAMs. Understanding these interactions may provide clues for developing new immunotherapy strategies.

Case Study

The study investigates how host genetics influences the tumor immune microenvironment (TIME) to inform cancer screening and treatment strategies. The researchers analyzed 1084 expression quantitative trait loci (eQTLs) related to TIME using data from The Cancer Genome Atlas and literature. These eQTLs are notably enriched in regions of active transcription and correlate with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. By constructing polygenic score models with these TIME eQTLs, the researchers successfully stratified cancer risk, survival, and immune checkpoint blockade (ICB) responses across independent cohorts.

Figure 2. Overview of the Tumor Immune Microenvironment germline analysis. (Pagadala M, et al., 2023)

Reference Ideas

1. Identify Key Genetic Variants: Utilize GWAS or eQTL analysis to pinpoint genetic variants impacting TIME and their association with immune cell gene expression.

2. Develop Polygenic Risk Models: Create models based on identified TIME eQTLs to predict cancer risk, survival outcomes, and response to immunotherapy, validating these models across various cohorts.

3. Screen and Validate Targets: Investigate potential immunotherapy targets revealed by eQTLs and polygenic models. Perform functional validation experiments, such as gene inhibition studies, to assess their impact on tumor progression and survival.

4. Integrate Omics Data: Combine genomic data with TIME characteristics to deepen understanding of immune regulation in cancer and enhance personalized treatment approaches.

3.2 Tumor Angiogenesis

Tumor angiogenesis is crucial for tumor growth and metastasis. Researchers are working to uncover the mechanisms by which tumor cells regulate angiogenesis, including the roles of various pro-angiogenic factors and how tumor cells alter endothelial cell behavior. These studies provide a theoretical basis for developing anti-angiogenesis drugs.

Case Study

The TME is one of the key factors contributing to the poor response of hepatocellular carcinoma (HCC) patients to current therapies, with tumor vascular endothelial cells (ECs) being a fundamental component that drives tumor progression. Researchers have unveiled the critical role of ECs within the TME in HCC, particularly highlighting the importance of endothelial diacylglycerol kinase γ (DGKG) in promoting tumor angiogenesis and immune evasion. Through spatially resolved single-cell analysis, it was found that DGKG is activated under hypoxic conditions by hypoxia-inducible factor-1α (HIF-1α). This activation recruits ubiquitin-specific peptidase 16 (USP16) to deubiquitinate zinc finger E-Box binding protein 2 (ZEB2), thereby activating a positive feedback loop involving transforming growth factor-β1 (TGF-β1), ultimately driving HCC progression. Notably, targeting DGKG enhanced the efficacy of the dual blockade of PD-1 and VEGFR-2, suggesting that DGKG could be a potential therapeutic target in HCC.

Figure 3. DGKG/USP16/ZEB2/TGF-β1 signaling axis or DGKG-mediated tumor angiogenesis and immune evasion mechanism. (Zhang L, et al., 2024)

Reference Ideas

1. Exploring the Regulatory Mechanisms of DGKG: Investigate the expression of DGKG in other tumor types and its relationship with HIF-1α to determine whether it plays a similar tumor-promoting role. Analyze whether DGKG also activates the ZEB2/TGF-β1 axis through similar mechanisms in other cancers.

2. Identifying Downstream Signaling Pathways of DGKG: Further explore the downstream molecules and pathways of DGKG through gene knockout and functional analysis, particularly focusing on its specific roles and mechanisms in immune evasion and angiogenesis.

3. Developing DGKG-Targeted Therapies: Given the critical role of DGKG in HCC, develop small molecule inhibitors or antibody drugs targeting DGKG and assess their antitumor efficacy in preclinical animal models.

4. Combined Therapeutic Strategies: Evaluate the synergistic effects of DGKG-targeted therapy with existing treatments, such as PD-1/PD-L1 immune checkpoint inhibitors and VEGFR-2 inhibitors, to optimize therapeutic regimens for HCC.

3.3 Cellular Metabolism

Metabolic changes in the tumor microenvironment affect the function of the tumor and immune cells. Researchers are exploring the relationship between tumor glycolysis and immune microenvironment remodeling. Understanding how these metabolic changes impact immune cell function may offer insights into developing new metabolic-targeted therapies.

Case Study

Xiongzhong Ruan et al. published a study in Nature Communications that reveals the impact of CD36-mediated metabolic crosstalk between tumor cells and macrophages on liver metastasis. The research found that tumor cells utilize CD36-mediated metabolic communication to transfer fatty acids to metastasis-associated macrophages (MAMs) via extracellular vesicles. This process promotes the metabolic and functional reprogramming of macrophages, which in turn supports tumor progression. The study also suggests that targeting CD36 may alleviate this metabolic dependence and associated immune suppression, providing a potential therapeutic target for the immunotherapy of liver metastasis.

Figure 4. Increased Lipid Deposition and CD36 Expression in MAMs. (Yang P, et al., 2022)

Reference Ideas

1. Exploring CD36 in Other Tumors: Investigate CD36's role in other cancers to determine if similar tumor-macrophage metabolic interactions exist.

2. Mechanism of Lipid Transfer: Study the specific mechanisms of lipid transfer from tumor cells to macrophages via extracellular vesicles to identify new therapeutic targets.

3. CD36-Targeted Therapy Development: Develop and test CD36 inhibitors or antibodies in preclinical models as potential cancer treatments.

4. Combination Therapy: Explore the synergy between CD36-targeted therapies and existing immunotherapies to enhance treatment outcomes.

5. Impact of Metabolic Reprogramming: Assess how CD36-driven macrophage reprogramming influences other immune cells and the tumor microenvironment.

6. Clinical Studies: Validate CD36 as a biomarker in liver metastasis patients to guide personalized treatment.

3.4 Cancer-Associated Adipocytes (CAA)

Recent attention has been given to the role of cancer-associated adipocytes in tumor progression. Researchers are investigating how factors secreted by CAAs promote tumor growth and metastasis. This research direction may provide new targets for therapeutic strategies targeting the tumor microenvironment.

Case Study

A research team from Shanghai Jiao Tong University School of Medicine published a study in Cell Death & Disease. The study highlights the crucial role of cancer-associated adipocytes (CAAs) and their derived CXCL8 in the progression of triple-negative breast cancer (TNBC). It was found that CXCL8 derived from CAAs not only suppresses the infiltration of CD4+ and CD8+ T cells but also upregulates CD274, thereby remodeling the tumor immune microenvironment. Targeting the CXCL8 pathway in combination with PD-1 inhibitors significantly enhances immune response and inhibits tumor progression.

Figure 5. CAA enhances TNBC cell proliferation, migration, and invasion in vitro. (Huang R, et al., 2023)

Reference Ideas

1. CAA and TNBC Cell Interactions: Investigate how CAAs affect TNBC cell proliferation, migration, and invasion, and study the underlying mechanisms, such as the activation of the EMT process and the PI3K/AKT pathway.

2. Role of CXCL8: Examine the specific effects of CXCL8 derived from CAAs on TNBC progression and metastasis, including its impact on tumor cell migration and invasion, and its modulation of immune responses.

3. Changes in Immune Microenvironment: Evaluate how CXCL8 influences immune cell infiltration, including CD4+ T cells, CD8+ T cells, macrophages, and neutrophils, and its contribution to the overall immune suppression.

4. Development of Therapeutic Strategies: Develop small molecule inhibitors or antibodies targeting CXCL8 based on its role in TNBC, and combine them with PD-1 inhibitors to assess their efficacy in suppressing tumor progression and enhancing immune response.

5. Clinical Translation: Validate the efficacy of targeting CXCL8 and PD-1 in clinical settings using TNBC patient tumor samples and 3D organoid models to assess the potential for clinical application.

3.5 Cancer-Associated Fibroblasts (CAFs)

CAFs are another significant cell population in the tumor microenvironment. Current research focuses on how exosomal miRNA secreted by CAFs regulates tumor progression. These miRNAs may play key roles in the communication between tumor cells and the microenvironment, offering potential new diagnostic biomarkers and therapeutic targets.

Case Study

In a recent study published in Molecular Cancer, the research team led by Dr. Qiang Feng at Shandong University investigated the crosstalk between cancer-associated fibroblasts (CAFs) and the tumor microenvironment (TME) across various cancers. Their research utilized spatially resolved single-cell transcriptomics to identify four distinct CAF subpopulations and analyze their spatial distribution within the TME. The study highlighted the role of matrix CAFs (mCAFs) in angiogenesis and inflammatory CAFs (iCAFs) in creating an immunosuppressive environment. Notably, iCAFs were shown to enhance cancer cell proliferation, epithelial-mesenchymal transition (EMT), and the development of an immunosuppressive microenvironment in breast cancer patients undergoing anti-PD-1 therapy. The study also revealed a significant correlation between iCAF-based scoring and response to immunotherapy in melanoma patients.

Figure 6. Pan-Cancer Spatial Single-Cell Transcriptome Atlas. (Ma C, et al., 2023)

Reference Ideas

1. CAF Subpopulation Analysis: Use spatial transcriptomics and scRNA-seq to identify and characterize CAF types across cancers.

2. CAF Functions: Investigate CAF roles in tumor growth, angiogenesis, and immune suppression.

3. CAF Impact on Immunity: Study how iCAFs affect immune cell function and therapy response.

4. Data Integration: Combine spatial and single-cell data to map CAF distribution and interactions in the TME.

5. Therapeutic Targeting: Explore therapies targeting specific CAF subpopulations and their combination with immunotherapies.

6. CAF Markers and Therapy Response: Develop markers based on CAF characteristics to predict treatment effectiveness.

Conclusion and Perspective

Research into the tumor microenvironment opens up new avenues for comprehending cancer's complexities. Our understanding of cancer is always evolving, from early genetic mutation ideas in cancer genesis to today's in-depth study of the intricate ecosystem of the tumor microenvironment. The interactions and spatiotemporal dynamics of many biological components in the tumor microenvironment provide a complicated and intriguing picture.

Current research directions, whether focused on specific immune cell populations, metabolic alterations, or specific stromal cells, disclose the secrets of the tumor microenvironment. These studies not only improve our understanding of cancer's nature, but they also provide several suggestions for developing new diagnostic and therapeutic approaches.

Looking ahead, as technology and research develop, tailored therapy techniques based on the tumor microenvironment will become more viable. By modifying the tumor microenvironment, we may be able to develop more effective strategies to suppress tumor growth, boost the body's anti-tumor immune response, and eventually improve cancer control. The study of the tumor microenvironment is a difficult but extremely promising field. It needs the integration of diverse knowledge, such as biology, immunology, and metabolism, as well as open and inventive thinking. As science advances, we anticipate revolutionary discoveries that will provide new hope to cancer patients.

Related Genes or Targets

Creative Biogene understands the intricacies of cancer research and provides specific products to help you develop your studies on the tumor microenvironment. Our extensive product selection meets your research demands, whether you're looking into hypoxia-induced gene expression or immune cell interactions.