Editorial: Volume II: tumour microenvironment in cancer research and drug discovery

Abstract

From being a passive backdrop, the tumour microenvironment (TME) is now recognised as a core 12 driver of cancer initiation, progression, metastasis, immune escape, and treatment response. As such, 13 there is a major shift from cancer-centric to TME-centric research, positioning TME as a hub for 14 therapeutic targets. Approved and experimental strategies are now directed towards various 15 components and conditions of the TME, including immune checkpoints, cancer-associated fibroblasts, 16ECM, and inflammatory niches, as well as processes like angiogenesis, metabolism, hypoxia, and 17 acidity (Goenka et al., 2023) aiming to advance precision oncology, inform prognostic biomarkers (eg. 18 Immunoscore), and optimize combination regimens in cancer management (Tonello et al., 2025). 19The intricate and interdependent network of tumour microenvironment (TME) components, together 20 with tumour heterogeneity, continues to establish key players within this complex ecosystem. In this 21 special issue, we highlight recent advances in overcoming the biological, immunological, and physical 22 barriers of the TME to enhance the efficacy of cancer treatments, particularly immunotherapy. to reprogramme an immune-tolerant TME into a hostile environment for tumour growth and survival. 67Beyond the manipulation of targetable molecule pathways, engineering therapeutics to overcome the 68 physical and fluid-dynamic barriers of the TME remains a significant challenge. Therapeutic delivery 69 to solid tumors is often hindered by elevated interstitial fluid pressure and a dense stroma architecture, 70 both of which severely restrict conventional pressure-driven drug perfusion. In this issue, a 71 computational reverse advection-diffusion (RAD) model reveals that exploiting electrohydrodynamic 72 (EHD) forces generated by the electric charge of the glycocalyx at the walls of tumor blood vessels 73 can actively drive plasma and therapeutic solutes across these physical barriers, thereby enhancing 74 perfusion into the tumor matrix. 75The integration of nanotechnology with immunological insights for immunotherapy delivery is also 76 explored, particularly through nanoscale delivery systems such as liposomes, dendrimers, and 77 polymeric nanoparticles. These platforms protect therapeutic payloads from enzymatic degradation 78 while enabling targeted delivery to immune cells, including CD4+ T cells. As a result, they minimize 79 off-target systemic toxicity and facilitate more effective penetration of therapeutics into the TME. 80Collectively, the studies featured in this issue underscore the growing shift towards synergistic and 81 multimodal therapeutic strategies to address the limitations of monotherapies in overcoming tumour 82 heterogeneity, compensatory escape mechanisms, and the complex resistance landscape of the