Cancer Bioenergetics and Tumor Microenvironments—Enhancing Chemotherapeutics and Targeting Resistant Niches through Nanosystems

SIMPLE SUMMARY: Cancer remains a major killer of the human population. Current cancer diagnostic and therapeutic methods are associated with shortcomings of limited targetability, specificity, solubility, and side effects. The therapeutic impediment is mainly attributed to the complex tumor microenvironments, which facilitate cancer progression. Additionally, the significant driver of tumorigenesis is mitochondria-centered energy metabolism. Bioenergetic alterations modulate the tumor microenvironment to help tumor progression and metastasis. In this review, we revisit the current understanding of mitochondrial bioenergetics mechanisms and tumor microenvironments that can be targeted through various nanoparticle-based smart systems. The nanosystems have gained momentum due to their high targetability and lower toxicity, and hence hold great potential in enhancing cancer chemotherapeutics. A liaison between nanoparticles and chemotherapeutic drugs can potentially target resistant cancers effectively for a successful therapeutic regime. ABSTRACT: Cancer is an impending bottleneck in the advanced scientific workflow to achieve diagnostic, prognostic, and therapeutic success. Most cancers are refractory to conventional diagnostic and chemotherapeutics due to their limited targetability, specificity, solubility, and side effects. The inherent ability of each cancer to evolve through various genetic and epigenetic transformations and metabolic reprogramming underlies therapeutic limitations. Though tumor microenvironments (TMEs) are quite well understood in some cancers, each microenvironment differs from the other in internal perturbations and metabolic skew thereby impeding the development of appropriate diagnostics, drugs, vaccines, and therapies. Cancer associated bioenergetics modulations regulate TME, angiogenesis, immune evasion, generation of resistant niches and tumor progression, and a thorough understanding is crucial to the development of metabolic therapies. However, this remains a missing element in cancer theranostics, necessitating the development of modalities that can be adapted for targetability, diagnostics and therapeutics. In this challenging scenario, nanomaterials are modular platforms for understanding TME and achieving successful theranostics. Several nanoscale particles have been successfully researched in animal models, quite a few have reached clinical trials, and some have achieved clinical success. Nanoparticles exhibit an intrinsic capability to interact with diverse biomolecules and modulate their functions. Furthermore, nanoparticles can be functionalized with receptors, modulators, and drugs to facilitate specific targeting with reduced toxicity. This review discusses the current understanding of different theranostic nanosystems, their synthesis, functionalization, and targetability for therapeutic modulation of bioenergetics, and metabolic reprogramming of the cancer microenvironment. We highlight the potential of nanosystems for enhanced chemotherapeutic success emphasizing the questions that remain unanswered.