Transforming Cancer Treatment: Integrative Strategies Targeting the Tumor Microenvironment through Biological Innovation and Artificial Intelligence.

Dynamic tumor microenvironment remodeling in cancer therapy resistance: molecular mechanisms and translational opportunities

Current insights into the molecular mechanisms underlying TME remodeling are summarized, including ECM mechanotransduction, hypoxia-driven signaling, hypoxia-driven signaling, epigenetic regulation, metabolic reprogramming, and extracellular vesicle-mediated communication.

Clinical Medicine and Integrative Therapies

Tumor-host metabolic interactions in the microenvironment and macroenvironment: Mechanisms and targeting strategies.

ABSTRACT Tumor metabolic reprogramming is a hallmark of cancer and is driven not only by intrinsic mechanisms of tumor cells but also by dynamic interactions between the local tumor microenvironment (TME) and the host macroenvironment. This review systematically elaborates on the central role of "tumor-host" metabolic crosstalk in reshaping both the TME and the broader host macroenvironment. In the TME, hypoxia, nutrient deprivation, metabolic waste accumulation, and metabolic interactions among immune and stromal cells collectively facilitate tumor adaptation to harsh conditions and drive tumor progression. Concurrently, host macroenvironmental factors, including the gut microbiota and its metabolites, adipose tissue, systemic chronic inflammation, and hormonal imbalances, remotely regulate tumor initiation and development through multiple mechanisms. We further summarize emerging therapeutic strategies targeting metabolic pathways and emphasize the future need to break down boundaries between microenvironments and macroenvironments, suggesting the need for multiscale metabolic interventions to improve cancer treatment efficacy.

Tumor Plasticity and Microenvironmental Crosstalk as Drivers of Metastasis and Therapy Resistance

Tumor plasticity and microenvironmental heterogeneity are established as an integrated, evolving system that fuels metastasis and limits durable treatment responses.

TUMOR MICROENVIRONMENT DYNAMICS: MOLECULAR AND GENETIC DETERMINANTS OF CANCER PROGRESSION AND THERAPY RESPONSE

The evidence demonstrates that growth factor signalling, inflammatory pathways, hypoxia, metabolic reprogramming, genetic and epigenetic alterations, and extracellular vesicle-mediated communication alter the tumour microenvironment, encouraging tumour growth, metastasis, immune escape, and resistance to immunotherapy, chemotherapy, radiation, and targeted treatment.

Angiocrine factors in tumor microenvironment: bidirectional crosstalk, mechanistic insights, and therapeutic strategies.

BACKGROUND Tumor recurrence, metastasis, and treatment resistance represent core challenges in clinical oncology closely associated with the complex and dynamic tumor microenvironment (TME). Endothelial cells (ECs), key components of the TME, have functions that extend far beyond the traditional concept of tumor angiogenesis. In recent years, extensive research has revealed that ECs perform endocrine and paracrine functions by secreting angiocrine factors. These factors have been shown to contribute to tumor progression through multiple mechanisms, including remodeling of the tumor vascular niche, tumor immune suppression, metabolic reprogramming, and chemotherapy resistance. Therefore, a deeper understanding of the functional characteristics and regulatory mechanisms of angiocrine factors is crucial for identifying effective therapeutic targets in cancer. MAIN BODY This review integrates research advances on angiocrine factors associated with tumor progression, categorizing them into several key functional domains on the basis of their biological characteristics. We summarize the core signaling pathways regulated by angiocrine factors, including the Notch and Wnt pathways, and their crosstalk networks. We further elucidate the regulatory role of angiocrine factors in endothelial metabolism. Additionally, we explore the multifaceted functions of angiocrine factors in tumor dormancy, metastasis (tumor metastasis mediated by endothelial necroptosis), stemness maintenance, and immune suppression. Notably, this review highlights the complex crosstalk between ECs and tumor cells (TCs), as well as the roles of Notch and Wnt signaling pathways in vascular formation and endothelial metabolic. Finally, we discuss the current clinical limitations of anti-angiogenic therapies and combination treatment strategies, while highlighting the therapeutic potential and challenges of a "one-target, multiple-effects" approach. CONCLUSION Angiocrine factors are central regulatory mediators that coordinate tumor progression. The complexity and redundancy of the angiocrine factor networks is not only the root of limitations in anti-vascular therapies but also present opportunities for "one-target, multiple-effects" strategies. Rapid advances in single-cell transcriptomics, spatial transcriptomics, and lineage tracing technologies now provide powerful tools to decipher the spatiotemporal heterogeneity of vascular secretory factors and to track the clonal evolution and functional transitions of endothelial cells and their progenitor cells. These advances offer the potential to precisely identify key therapeutic targets, facilitating the development of novel anti-angiogenic strategies.