The deep and inner beds of solid tumors lack lymphocytic infiltration and are subjected to various immune escape mechanisms. Reversing immunosuppression deep within the tumor is vital in clinical cancer therapy, however it remains a huge challenge. In this work, we have demonstrated the use of a second window nearinfrared (NIR(II)) photothermal treatment to trigger more homogeneous and deeper immunogenic cancer cell death in solid tumors, thereby eliciting both innate and adaptive immune responses for tumor control and metastasis prevention. Specifically, photothermal transducers with similar components, structures, and photothermal conversion efficiencies, but different absorptions in red light, NIR(I), and NIR(II) biowindows, were constructed by controlling the selfassembly of gold nanoparticles on fluidic liposomes. In vitro, photothermal treatments induced immunogenic cell death (ICD) that were accompanied by the release of damage-associated molecular patterns (DAMPs) regardless of the wavelength of incident lasers. In vivo, NIR(II) light resulted in a more homogeneous release and distribution of DAMPs in the deeper parts of the tumors. With the induction of ICD, NIR(II) photothermal therapy simultaneously triggered both innate and adaptive immune responses and enabled efficient tumor control with 5/8 of the mice remaining tumor-free in the cancer vaccination assay. Additionally, the NIR(II) photothermal treatment in combination with checkpoint blockade therapy exerted long-term tumor control over both primary and distant tumors. Finally, using systemically administered twodimensional polypyrrole nanosheets as a NIR(II) transducer, we achieved striking therapeutic effects against whole-body tumor metastasis via a synergistic photothermal-immunological response.

While tumor-infiltrating cytotoxic T lymphocytes play a critical role in controlling tumor development, they are generally impotent in an acidic tumor microenvironment. Systemic treatment to neutralize tumor acidity thus holds promise for the reversal of the anergic state of T cells and the improvement of T cell-associated immunotherapy. Herein, we report a proof-of-concept of RNAi nanoparticle-mediated therapeutic reversion of tumor acidity to restore the antitumor functions of T cells and potentiate the checkpoint blockade therapy. Our strategy utilized an in vivo optimized vesicular cationic lipid-assisted nanoparticle, as opposed to its micellar counterpart, to mediate systematic knockdown of lactate dehydrogenase A (LDHA) in tumor cells. The treatment resulted in the reprogramming of pyruvate metabolism, a reduction of the production of lactate, and the neutralization of the tumor pH. In immunocompetent syngeneic melanoma and breast tumor models, neutralization of tumor acidity increased infiltration with CD8+ T and NK cells, decreased the number of immunosuppressive T cells, and thus significantly inhibited the growth of tumors. Furthermore, the restoration of tumoral pH potentiated checkpoint inhibition therapy using the antibody of programmed cell death protein 1 (PD-1). However, in immunodeficient B6/Rag1 –/– and NOG mice, the same treatment failed to control tumor growth, further proving that the attenuation of tumor growth by tumor acidity modulation was attributable to the activation of tumor-infiltrating immune cells.

Growth signals, such as extracellular nutrients and growth factors, have significant impacts on genome integrity, while the direct underlying link remains unclear. Here we show that the mechanistic target of rapamycin (mTOR)-ribosomal S6 kinase (S6K) pathway, a central regulator of growth signaling, phosphorylates RNF168 at Ser60 to inhibit its E3 ligase activity, accelerate its proteolysis, and impair its function in DNA damage response, leading to accumulated unrepaired DNA and genome instability. Moreover, loss of the tumor suppressor LKB1/STK11 hyper-activates the mTORC1-S6K signaling and decreases RNF168 expression, resulting in defects of DNA damage response. Expression of a phospho-deficient RNF168 (S60A) mutant rescues the DNA damage repair defects and suppresses tumorigenesis caused by Lkb1 loss. These results reveal an important function of the mTORC1-S6K signaling in DNA damage response and suggest a general mechanism connecting cell growth signaling to genome stability control.

Background: As a neutral lipid and prominent component of the Western diet, cholesterol levels might be a risk factor for prostate cancer. However, current evidence has been inconsistent. This meta-analysis aimed to evaluate the association between blood cholesterol levels and the risk of prostate cancer.Methods: An extensive search was performed in MEDLINE and EMBASE for prospective studies that have reported the association between total cholesterol (TC), high-density lipoprotein cholesterol (HDL), and low-density lipoprotein cholesterol (LDL) levels in blood and risk of prostate cancer. Random-effects models were used to summarize the study-specific results.Results: Fourteen studies were included in this meta-analysis. In the meta-analysis, the summarized risk ratios (RR) for the highest to lowest cholesterol levels were as follows: 1.05 [95%

Cholesterol biosynthesis is regulated by transcription factors SREBPs and their escort protein Scap. On sterol depletion, Scap/SREBP complex is transported from endoplasmic reticulum (ER) to the Golgi apparatus where SREBP is activated. Under cholesterol sufficient condition, Insigs act as anchor proteins to retain Scap/SREBP in the ER. However, the anchor protein of Scap/SREBP in the Golgi is unknown. Here we report that a Golgi-localized membrane protein progestin and adipoQ receptors 3 (PAQR3) interacts with Scap and SREBP and tethers them to the Golgi. PAQR3 promotes Scap/SREBP complex formation, potentiates SREBP processing and enhances lipid synthesis. The mutually exclusive interaction between Scap and PAQR3 or Insig-1 is regulated by cholesterol level. PAQR3 knockdown in liver blunts SREBP pathway and decreases hepatic cholesterol content. Disrupting the interaction of PAQR3 with Scap/SREBP by a synthetic peptide inhibits SREBP processing and activation. Thus, PAQR3 regulates cholesterol homeostasis by anchoring Scap/SREBP to the Golgi and disruption of such function reduces cholesterol biosynthesis.