Healthcare, as a basic human right, has often become the focus of the development of innovative technologies. Technological progress has significantly contributed to the provision of high-quality, on-time, acceptable, and affordable healthcare. Advancements in nanoscience have led to the emergence of a new generation of nanostructures. Each of them has a unique set of properties that account for their astonishing applications. Since its inception, nanotechnology has continuously affected healthcare and has exerted a tremendous influence on its transformation, contributing to better outcomes. In the last two decades, the world has seen nanotechnology taking steps towards its omnipresence and the process has been accelerated by extensive research in various healthcare sectors. The inclusion of nanotechnology and its allied nanocarriers/nanosystems in medicine is known as nanomedicine, a field that has brought about numerous benefits in disease prevention, diagnosis, and treatment. Various nanosystems have been found to be better candidates for theranostic purposes, in contrast to conventional ones. This review paper will shed light on medically significant nanosystems, as well as their applications and limitations in areas such as gene therapy, targeted drug delivery, and in the treatment of cancer and various genetic diseases. Although nanotechnology holds immense potential, it is yet to be exploited. More efforts need to be directed to overcome these limitations and make full use of its potential in order to revolutionize the healthcare sector in near future.

The cell autonomous balance of immune-inhibitory and -stimulatory signals is a critical yet poorly understood process in cancer immune evasion. Using patient-derived co-culture models and humanized mouse models, we show that an intact CD58:CD2 interaction is necessary for anti-tumor immunity. Defects in this axis lead to multi-faceted immune evasion through impaired CD2-dependent T cell polyfunctionality, T cell exclusion, impaired intra-tumoral proliferation, and concurrent protein stabilization of PD-L1. We performed genome-scale CRISPR-Cas9 and CD58 co-immunoprecipitation mass spectrometry screens identifying CMTM6 as a key stabilizer of CD58, and show that CMTM6 is required for concurrent upregulation of PD-L1 in CD58 loss. Single-cell RNA-seq analysis of patient melanoma samples demonstrates that most TILs lack expression of primary co-stimulatory signals required for response to PD-1 blockade (e.g. CD28), but maintain strong CD2 expression, thus providing an opportunity to mobilize a so far therapeutically untapped pool of TILs for anti-tumor immunity. We identify two potential therapeutic avenues, including rescued activation of human CD2-expressing TILs using recombinant CD58 protein, and targeted disruption of PD-L1/CMTM6 interactions. Our work identifies an underappreciated yet critical axis at the nexus of cancer immunity and evasion, uncovers a fundamental mechanism of co-inhibitory and -stimulatory signal balancing, and provides new approaches to improving cancer immunotherapies.

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