Major fundamental factors hindering immune system in defense against tumor cells: The link between insufficiency of innate immune responses, metabolism, and neurotransmitters with effector immune cells disability

Despite the major progresses in comprehending the mechanisms of tumor immunosurveillance and the role of
innate and adaptive immune systems in recent years, there are still a number of obstacles hindering successful
and effective immunotherapy of cancer. Such obstacles have been mainly attributed to the ability of tumors in
creating a tolerant microenvironment and exploiting a plethora of immunosuppressive factors that counter effective
immune responses against tumor cells. Here we represent a new insight into probable links between
immune system disability with metabolism and chronic psychological stress which is beyond the other strategies
recruited by tumors to thwart tumor immunosurveillance. In addition, we underscore the prominent role of
improper innate immune responses as one of the underlying causes of either pro-tumorigenic capability or tumor
immunosurveillance failure. However the insufficiency of stimulatory factors in immune responses is a major
fact leading to tumor survival, metabolic suppression of immune cells in tumor microenvironment, as well as the
negative influences of chronic stress and depression in cancer patients are important parameters amplifying
disability of immune responses which have mostly been underestimated in cancer immunotherapy. Stress-related
catecholamines are suggested as immunosuppressive factors. In addition, tumor cells have distinct metabolic
pathways and secrete various metabolites in the tumor microenvironment which may inhibit T cells activity. We
believe that simultaneous control of metabolic and psychological negative influences on the tumor immunosurveillance,
along with addressing the weak aspects of innate and adaptive immune responses in cancer
immunotherapy may result in more successful treatment of tumors.