Immune evader cancer stem cells direct the perspective approaches to cancer immunotherapy.

Exploration of tumor immunity leads to the development of immune checkpoint inhibitors and cell-based immunotherapies which improve the clinical outcomes in several tumor types. However, the poor clinical efficacy of these treatments observed for other tumors could be attributed to the inherent complex tumor microenvironment (TME), cellular heterogeneity, and stemness driven by cancer stem cells (CSCs). CSC-specific characteristics provide the bulk tumor surveillance and resistance to entire eradication upon conventional therapies. CSCs-immune cells crosstalk creates an immunosuppressive TME that reshapes the stemness in tumor cells, resulting in tumor formation and progression. Thus, identifying the immunological features of CSCs could introduce the therapeutic targets with powerful antitumor responses. In this review, we summarized the role of immune cells providing CSCs to evade tumor immunity, and then discussed the intrinsic mechanisms represented by CSCs to promote tumors' resistance to immunotherapies. Then, we outlined potent immunotherapeutic interventions followed by a perspective outlook on the use of nanomedicine-based drug delivery systems for controlled modulation of the immune system.

NK cells-directed therapies target circulating tumor cells and metastasis.

Metastasis is the major cause of cancer-related deaths. Invasive primary cancers often metastasize after circulating tumor cells (CTCs) enter the bloodstream or lymph node to colonize adjacent tissue or distant anatomical locations. CTCs interact with immune cells and metastatic microenvironments, survival signaling, and chemotherapeutic resistance. Among immune cells, natural killer (NK) cells can, directly and indirectly, interact with CTCs to control cancer metastasis. Understanding the molecular mechanisms that drive NK cells mediated recognition and elimination of CTCs may pave the way for a new generation of anti-CTC molecularly targeted immunotherapies. In this review, we will discuss i) the role of CTCs in metastases, ii) CTCs in the context of the tumor microenvironment, iii) CTCs immune escape, and finally, iv) the potentials of NK cell-based therapies alone, or in combination with nanomedicine for targeted-immunotherapies of metastatic diseases.

TRAIL in oncology: From recombinant TRAIL to nano- and self-targeted TRAIL-based therapies.

TNF-related apoptosis-inducing ligand (TRAIL) selectively induces the apoptosis pathway in tumor cells leading to tumor cell death. Because TRAIL induction can kill tumor cells, cancer researchers have developed many agents to target TRAIL and some of these agents have entered clinical trials in oncology. Unfortunately, these trials have failed for many reasons, including drug resistance, off-target toxicities, short half-life, and specifically in gene therapy due to the limited uptake of TRAIL genes by cancer cells. To address these drawbacks, translational researchers have utilized drug delivery platforms. Although, these platforms can improve TRAIL-based therapies, they are unable to sufficiently translate the full potential of TRAIL-targeting to clinically viable products. Herein, we first summarize the complex biology of TRAIL signaling, including TRAILs cross-talk with other signaling pathways and immune cells. Next, we focus on known resistant mechanisms to TRAIL-based therapies. Then, we discuss how nano-formulation has the potential to enhance the therapeutic efficacy of TRAIL protein. Finally, we specify strategies with the potential to overcome the challenges that cannot be addressed via nanotechnology alone, including the alternative methods of TRAIL-expressing circulating cells, tumor-targeting bacteria, viruses, and exosomes.