SUMMARY Advances in unleashing the immune system against patients' tumors has altered the clinical landscape for recently thought untreatable advanced stage cancers, such as melanoma, bladder carcinoma, and non- small cell lung cancer. For immune checkpoint treatment to be effective, however, there must be a pre- existing ability for immune cells to recognize the cancer, which relates to the tumor itself and wherein a high genetic mutation burden result in antigenic peptides that are recognized as foreign. In effect, immune checkpoint blocking anti-cancer therapeutics exploit and release pre-existing inflammatory signals directed against the tumors' neoantigens. The barriers to achieving long-term durable treatment and broadening the observed responses are however currently largely unknown. Nevertheless, it is intuitive that a low neoantigen burden, or their reduced overall expression, blunt the therapeutic responses and may consequently also enable treatment progression. To this end, we have set out to define tumor inherent molecular cascades that impact a cancer's immunogenicity and that may modulate effects of immune checkpoint treatment. In preliminary studies we have found that transcriptional cues involved in cell-fate determination and differentiation are reduced in tumors that have evolved to circumvent immune recognition. Guided by the fact that tumor-antigens are critical to immune-surveillance, elevating their inherent levels by increasing lineage-specific transcriptional circuits may promote consequent tumor recognition and destruction. In two specific aims, we will a) determine how lineage-specific transcriptional regulation is coordinated with metabolic cues to alter a transcriptional repertoire that is associated with reduced antigenicity; and b) provide proof-of-concept for elevating antigenicity of tumors to enhance immune checkpoint blockage responses. Successful completion of the proposed studies may improve our understanding of how tumors co-evolve to evade immune recognition and drive progression. In addition, our work may also provide critical pathway knowledge that could be used for therapeutic exploit.