Elevated infiltration of immunosuppressive alternatively polarized (M2) macrophages is associated with poor prognosis in patients with cancer. The tumor microenvironment remarkably orchestrates molecular mechanisms that program these macrophages. Here we identify a novel role for oncogenic Hedgehog (Hh) signaling in programming signature metabolic circuitries that regulate alternative polarization of tumor-associated macrophages. Two immunocompetent orthotopic mouse models of mammary tumors were used to test the effect of inhibiting Hh signaling on tumor-associated macrophages. Treatment with the pharmacologic Hh inhibitor vismodegib induced a significant shift in the profile of tumor-infiltrating macrophages. Mass spectrometry-based metabolomic analysis showed Hh inhibition induced significant alterations in metabolic processes, including metabolic sensing, mitochondrial adaptations, and lipid metabolism. In particular, inhibition of Hh in M2 macrophages reduced flux through the UDP-GlcNAc biosynthesis pathway. Consequently, O-GlcNAc-modification of STAT6 decreased, mitigating the immune-suppressive program of M2 macrophages, and the metabolically demanding M2 macrophages shifted their metabolism and bioenergetics from fatty acid oxidation to glycolysis. M2 macrophages enriched from vismodegib-treated mammary tumors showed characteristically decreased O-GlcNAcylation and altered mitochondrial dynamics. These Hh-inhibited macrophages are reminiscent of inflammatory (M1) macrophages, phenotypically characterized by fragmented mitochondria. This is the first report highlighting the relevance of Hh signaling in controlling a complex metabolic network in immune cells. These data describe a novel immunometabolic function of Hh signaling that can be clinically exploited. Significance: These findings illustrate that Hh activity regulates a metabolic and bioenergetic regulatory program in tumor-associated macrophages that promotes their immune-suppressive polarization.

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Optical coherence tomography (OCT) is a rapidly evolving, robust technology that has profoundly changed the practice of medical imaging. Swept source OCT (SSOCT) combines the standard time domain and the spatially encoded frequency domain OCT. We have employed a high-speed SSOCT system that utilizes a swept source laser with an A-scan rate of 100 kHz and a central wavelength of 1060 nm for the imaging of the tissue. SSOCT at 1060 nm allows for high penetration in the tissue. TiO 2 nanoparticles (NPs) are mostly used for various experimental purposes as an exogenous imaging contrast agent. The in vitro imaging of chicken breast tissue is performed with and without the application of TiO 2 NPs for exogenous contrast. Characterization of the chemically synthesized TiO 2 NPs was done with dynamic light scattering and a scanning electron microscope method. The effect of TiO 2 is studied at different exposure times. A significant improvement in the contrast to noise ratio has been observed through the in vitro imaging of a TiO 2 treated tissue.

The metabolic reprogramming of cell is a well‐established clinical hallmark of cancer and accordingly has attracted significant attention from researchers in the field of drug discovery. The dependency of cancer cells toward altered “cancer metabolism” (CM) encouraged scientists to work to better understand their metabolic alteration and tumor microenvironment. In fact, the cellular energetics of cancer cells is significantly different from normal cells due to the high demand of energy and metabolites that are required for cancer cell growth and proliferation. A combination of identification of metabolic processes and detailed study of how oncogenic signaling pathways can modulate the metabolic processes might be useful to achieve the selective killing of cancer cells. Recently, several studies have confirmed that cancer metabolism plays a fundamental role in cancer progression and metastasis. Carbohydrate metabolism, particularly glucose metabolism in tumor cells, has received significant attention because rapidly growing cancer cells preferentially rely on the enhanced rate of tumor glycolytic process uncoupled with oxidative phosphorylation. Small molecules targeting tumor glycolysis hold promise for drug discovery and drug development in cancer therapeutics. In addition, it offers the development of new treatment options by synergizing potential glycolytic inhibitors with existing drugs. Therefore, this article includes recent updates on tumor glycolysis and small molecules that counteract tumor glycolysis.

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