Purpose <p>Treatment of cancer is hindered by tumor heterogeneity, abnormal physiology, and barriers to drug delivery. Biomechanical forces in the tumor microenvironment, such as ECM rigidity, solid stress, and interstitial fluid pressure, play an important role in cancer progression and response to treatment as well. The objective of this review is to integrate tumor biomechanics with nanotechnology-based drug delivery systems, emphasizing mechano-responsive strategies for improving cancer treatment.</p> Methods <p>Recent studies have been critically analyzed regarding the biomechanical regulation of tumor growth, remodeling of the ECM, and the influence of mechanical stresses on therapeutic efficacy. In particular, nanoparticle mechanical properties, stiffness tuning, and mechanoresponsive DDSs triggered by endogenous and exogenous forces (ultrasound, magnetic fields) were examined.</p> Results <p>The results suggest that biomechanical factors significantly influence drug transport, tumor progression, and treatment outcomes. Nanoparticle stiffness influences circulation, penetration, and uptake, while mechano-responsive systems enable spatiotemporal drug release. While exogenous stimuli have demonstrated promising translation into preclinical models, little research has been conducted on endogenous biomechanical triggers.</p> Conclusions <p>Biomechanics can be incorporated into drug delivery design to offer a novel approach to overcoming cancer therapy barriers. This review focuses on bridging tumor mechanobiology with nanomedicine, emphasizing the importance of exploiting biomechanical cues for precision oncology, optimizing nanoparticle design, and developing mechano-adaptive, patient-specific DDSs.</p> Future Work <p>To achieve more precise and adaptive drug delivery, future research should integrate patient-specific tumor mechanical profiles with stiffness-tuned and mechano-responsive nanocarriers. The therapeutic potential of endogenous biomechanical forces, which remain understudied compared to exogenous triggers, needs particular attention. A key component of translating biomechanical strategies into personalized cancer treatments will be the development of non-invasive imaging and monitoring tools capable of mapping tumor mechanics in real time.</p> Lay Summary <p>The physical characteristic inside tumors—such as tissue stiffness, fluid pressure, and solid stress—has a significant impact on both tumor growth and drug delivery during cancer treatment. This review describes how these forces influence both tumor growth and drug delivery. Additionally, the article addresses how tiny particles (nanoparticles) can be designed to respond to these forces, thereby improving the way treatments reach tumors. By combining biomechanics with drug delivery research, new strategies can be developed to enhance the effectiveness and personalization of cancer treatments.</p>