Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with a 5-year survival rate under 10%. Current treatments for PDAC are based on ineffective and unspecific drugs that cause hard side effects. Besides, new T cell-based immunotherapies are toxic and unsuccessful in most solid tumors, including PDAC. Activating KRAS mutations occur in almost all patients, but unfortunately, KRAS is difficult to target. This discouraging situation highlights the need to design orthogonal and innovative strategies that target different pro-tumoral axes, in order to increase the antitumor effect minimizing side effects. In NIR-NanoCAR project, we will develop a new concept of therapy, Near-Infrared (NIR) Photothermal Nano-CAR Immunotherapy (NIR-PNCI). To test this concept, we will fuse i) thermosensitive liposomes capable to mediate photothermal therapy by NIR, with ii) exosomes derived from mesothelin-CAR T cells armored with IL-12 (which maintain effector molecules from their parental cells) and loaded with siRNA targeted to mutated KRAS. We will explore the antitumor capability and the tumor microenvironment-reprograming mediated by the hybrid nanotherapy in a relevant murine PDAC model. If successful, this nanosystem will be a breakthrough with a paradigm shift in the strategy to design the next generation of nanoimmunotherapies for solid tumors.