<p>Lung squamous cell carcinoma (LUSC), a subtype of non-small cell lung cancer, exhibits significant therapeutic challenges, among others, due to the lack of known driver mutations as well as the development of drug resistance. In LUSC, the extracellular matrix (ECM), closely linked to dynamic changes in the tumor microenvironment (TME), plays a key role in regulating tumor immunity, through complex interactions among these components. These interactions drive the emergence of resistance mechanisms, including hypoxia-induced adaptive responses, immune evasion, and ECM and TME remodeling, which collectively contribute to reduced treatment efficacy and tumor persistence. Furthermore, cancer-associated fibroblasts and tumor-associated macrophages promote the proliferation and survival of tumor cells by forming protective barriers around them. Understanding the complex crosstalk between LUSC cells and their microenvironment is crucial for developing novel therapeutic strategies that aim to overcome drug resistance. This review highlights the latest findings on the role of the TME in therapy resistance and discusses potential targets for improving treatment outcomes in this cancer type.</p>