<p>Cancer is a leading cause of death globally, with resistance to therapy representing a major obstacle to effective treatment. The tumor microenvironment (TME), comprising a complex network to cellular and non-cellular components including cancer-associated fibroblasts, immune cells, the extracellular matrix and region of hypoxia, is integral to cancer progression and therapeutic resistance. This review delves into the multifaceted interactions within the TME that contribute to tumor growth, survival and immune evasion. Key elements such as the role of cancer- associated fibroblasts in remodeling the extracellular matrix and promoting angiogenesis, the influence of immune cells such as tumor-associated macrophages in creating an immunosuppressive milieu and the impact of hypoxia conditions on metabolic adaptation and therapy resistance are thoroughly examined. This review evaluates current and emerging TME-targeted therapeutic strategies, including inhibitors of extracellular matrix components, modulators of immune cell activity and approached to alleviate hypoxia. Combination therapies that integrate TME-targeted agents with conventional treatments such as chemotherapy and immunotherapy are also discussed for their potential to enhance treatment efficacy and circumvent resistance mechanisms. By synthesising recent advances in TME research and therapeutic innovation, this paper aims to underscore the importance of TME in cancer therapy and highlight promising avenues for improving patient outcomes through targeted intervention.</p> Graphical abstract <p>Tumor microenvironment and resistance: cellular and non-cellular components driving therapy resistance. The dynamic interplay between cellular and non-cellular components of the tumor microenvironment (TME) and their contribution to cancer therapy resistance. Cellular components include cancer-associated fibroblasts (CAFs), immune cells such as tumor-associated macrophages (TAMs) and stromal cells such as mesenchymal stem cells and pericytes, all of which modulate tumor growth, angiogenesis, extracellular matrix (ECM) remodelling and immune suppression. Non-cellular components include ECM, hypoxia and exosomes, which influences tumor progression, metastasis, immune evasion and impact drug delivery. Key resistance mechanisms are highlights, including ECM structural barriers, hypoxia-mediated survival pathways (via HIF1 and HIF2) and exosome-mediated intercellular communication. Therapeutic strategies aimed at targeting these TME components, including ECM-targeted therapies, immune modulation and hypoxia alleviation to overcome tumor resistance and improve therapeutic outcomes.</p> <p></p>