Optogenetic Immunomodulation: Shedding Light on Antitumor Immunity

Immunomodulatory therapies constitute a new pillar of anticancer therapy. Currently, cancer immunotherapy is associated with on-target, off-tumor cytotoxicity or immune-related adverse events. Thus, smarter immunotherapies with enhanced safety and precise control over the anticancer immune response are needed. Optoimmunoengineering will confer light sensitivity to the immune signaling network to enable remote and noninvasive control of both innate and adaptive immune responses with high spatiotemporal precision. Optogenetics can be made wireless by implanting miniature light-delivery devices into peripheral lymph nodes or by using red-shifted variants of optical actuators that are capable of penetrating deeper into biological tissues. Next-generation injectable, aqueous, soluble nano-optical systems are emerging for in vivo applications of optogenetics in the immune system. Microbial opsin-based optogenetic tools have been transformative for neuroscience. To extend optogenetic approaches to the immune system to remotely control immune responses with superior spatiotemporal precision, pioneering tools have recently been crafted to modulate lymphocyte trafficking, inflammasome activation, dendritic cell (DC) maturation, and antitumor immunity through the photoactivation of engineered chemokine receptors and calcium release-activated calcium channels. We highlight herein some conceptual design strategies for installing light sensitivities into the immune signaling network and, in parallel, we propose potential solutions for in vivo optogenetic applications in living organisms with near-infrared light-responsive upconversion nanomaterials. Moreover, to move beyond proof-of-concept into translational applications, we discuss future prospects for integrating personalized immunoengineering with optogenetics to overcome critical hurdles in cancer immunotherapy. Microbial opsin-based optogenetic tools have been transformative for neuroscience. To extend optogenetic approaches to the immune system to remotely control immune responses with superior spatiotemporal precision, pioneering tools have recently been crafted to modulate lymphocyte trafficking, inflammasome activation, dendritic cell (DC) maturation, and antitumor immunity through the photoactivation of engineered chemokine receptors and calcium release-activated calcium channels. We highlight herein some conceptual design strategies for installing light sensitivities into the immune signaling network and, in parallel, we propose potential solutions for in vivo optogenetic applications in living organisms with near-infrared light-responsive upconversion nanomaterials. Moreover, to move beyond proof-of-concept into translational applications, we discuss future prospects for integrating personalized immunoengineering with optogenetics to overcome critical hurdles in cancer immunotherapy. a therapy that harnesses the power of a patient's own immune system to fight cancer, with the goal of achieving complete and long-lasting cures for patients with cancer. Newly developed therapeutic options include monoclonal antibodies, cancer vaccines, immune checkpoint inhibitors, and chimeric antigen receptor based T-cell (CAR-T) therapy. engineered receptors that are present on the surface of T cells to enable specific recognition of tumor antigens. channel that is activated when the calcium ions are depleted from the endoplasmic reticulum of mammalian cells. A CRAC channel, comprising two major protein families called ORAI and STIM, is required for generating a productive immune response. CRAC channel dysfunction often leads to severe combined immunodeficiency. key molecules hardwired into the immune signaling network that act as either costimulatory or inhibitory signals to modulate immune response. Checkpoint blockade therapy (e.g., anti-CTLA4 or anti-PD-1 monoclonal antibodies) that targets regulatory pathways in T cells has been developed to overcome the immunosuppressive tumor microenvironment and, thus, to enhance antitumor immune response. a photoactivatable calcium entry platform engineered from a CRAC channel by installing light sensitivities into the cytosolic domain of stromal interaction molecule 1 (STIM1). The light-mediated conformational switch within engineered STIM1 molecules enables reversible opening of ORAI calcium channels on the plasma membrane. also called optogenetic immunomodulation, combines the use of optical and genetic approaches to remotely control the activities of ion channels and/or signaling components in cells of the immune system, thereby enabling phototunable modulation of innate and/or adaptive immunity at high spatiotemporal resolution. unidirectional movement of a cell in response to light-induced activation of chemokine receptor pathways along a light gradient in a way similar to a chemokine gradient. a specialized type of lanthanide ion-doped nanoparticle that exhibits anti-Stokes luminescence by converting low-energy deep tissue penetrable near-infrared light (NIR) into shorter wavelength emissions (e.g., NIR, visible, or ultraviolet) with higher energy. When paired with optogenetic tools based on ChR2 or LOV2, these nanoparticles can act as in situ nanoilluminators to activate light-sensitive modules with NIR light.