Promises and challenges for targeting the immunological players in the tumor micro-environment – Critical determinants for NP-based therapy

Immunotherapy holds great promises to address an effective and durable therapeutic response in a wider range of cancer types. However, the understanding of the complex immune biology interactions within the Tumour Immune Microenvironment (TiME) is limited. This aspect, coupled with the unmet challenges pertaining to the development and testing of drug delivery modes and operations, has overall resulted in a large attrition rate with few anti-cancer therapeutics reaching the clinic. Also, a thorough understanding of the cellular features of the other components of the TiME in terms of the spatial and temporal heterogeneity of the cell types, stoichiometries, functional states will further aid in expediting the drug discovery process. Better understanding of the evolving immunological players within the Tumour Microenvironment (TME), that dictate the process of evasion governed by the tumours, will present opportunities for targeted interventions, including those involving NP-based delivery strategies. Moreover, development of more physiologically relevant models requires the utilization of ex vivo patient-specific materials or traditional cell line-based mono and/or heterotypic culture models that can recapitulate the TiME. Such models can be used to test potential drug candidates, including NP (nanoparticle)-based drug delivery constructs for their targetability, deep tumor penetration as well as the pharmacological responses efficiently and expeditiously. NP-based drug delivery requires the passage of the NP-drug conjugate through various anatomical and pathological barriers, before it reaches its site of action. One of the determinants affecting biodistribution, transport, uptake and clearance involves the dynamic protein corona (PC) around the NP that confers a new “biological identity”. Hence, the PC should be modelled using systems that will recapitulate their in vivo formation, evolution and turnover, aside from the employment of analytical tools for their characterization. In summary, this review focuses on elucidation of TiME composition, advancements in in vitromodeling of TiME constitution, various treatment strategies and nanocarrier approaches to counter adverse TiME for enhancement of drug efficacy in order to improve clinical response.