Tumor immunotherapy currently centers on two main approaches.  The first is the use of "checkpoint" blockade antibodies to relieve PD-1 and CTLA-4 mediated immunosuppression of a patient's T cells, so that they become able to kill the tumor.  This strategy essentially provides an adjuvant that unlocks the endogenous anti-tumor immune response.  The second approach, cellular immunotherapy, involves administering cytolytic lymphocytes that act directly as anti-tumor effectors.  Most prominent in this category is the use of chimeric antigen receptor (CAR) T cells, that have been genetically modified to specifically target the patient's tumor.  The remarkable success of these approaches for treating a variety of cancers has generated tremendous hope and excitement, yet a number of issues remain.  For example, checkpoint blockade is not always effective, or in some cases can result in highly damaging immune attacks on healthy organs.  There are also concerns about the time required to generate genetically modified CAR-T cells that are individually tailored for each patient, as well as the cost and long-term safety of this strategy.  Here we have investigated using CD4⁺ iNKT cells as a cellular immunotherapy, since prior studies in murine models have suggested that these cells have powerful adjuvant-like functions that can activate antigen-specific MHC-restricted T cell responses.  To do this, we used a pre-clinical model of human B lymphomagenesis in vivo, in which human umbilical cord blood cells are transferred into immune-deficient NSG mice, and infected with the Epstein-Barr virus (EBV).  This results in the de novo formation of human B lymphomas in the mice over a period of 3-4 weeks.  Importantly, lymphomagenesis occurs in the presence of cognate human T cells that invade the tumors, but that usually fail to control them due to inhibition via PD-1 and CTLA-4.  This system thus allows for the analysis of iNKT cell immunotherapy in the context of an immunosuppressive environment that has silenced the endogenous T cells.  Administration of a single dose of CD4⁺ iNKT cells, with no added antigen, results in significantly reduced tumor burden in this model.  Remarkably, the iNKT cell immunotherapy is effective at late time points (i.e. after tumor masses are already well-established and infiltrated by T lymphocytes), but shows little or no effect if the iNKT cells are administered at earlier time points (i.e. when EBV-infected cells are present but before tumor masses are evident).  Further supporting an adjuvant-like effect by the iNKT cell immunotherapy, splenic T cells harvested from iNKT-treated but not PBS-treated control mice showed EBV-specific responses upon re-challenge with synthetic peptides in vitro.  These results suggest that CD4⁺ iNKT cells, which typically show much less cytotoxic function than their double-negative iNKT counterparts, nevertheless may mediate potent anti-tumor responses by activating endogenous effectors.  The adjuvant-like functions of CD4⁺ iNKT cells may thus provide an option for cellular immunotherapy that is independent of genetic modification, and that may synergize with other immunotherapeutic methods.