ABSTRACT This supplement is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 22-054. Therapeutic strategies based on traditional, complementary, and alternative medicine (TCAM) have emerged as a potential treatment option for cancer, especially in low- and middle-income countries (LMICs) with limited access to advanced technologies. However, the impact of well-controlled TCAM-based treatments in the modulation of protective anti-tumor immunity in cancer patients remains poorly defined. Expansion of myeloid- derived suppressor cells (MDSC) in tumor-bearing hosts represents a primary mechanism to limit protective anti- tumor T cell immunity and a major obstacle to the success of cancer immunotherapy. It is therefore imperative to develop new effective therapeutic strategies to overcome the immune restricting effects induced by MDSC in tumors. Our recent studies demonstrated that MDSC in tumors activate an integrated signaling network known as the unfolded protein responses (UPR) as a reaction to the sustained and pronounced endoplasmic reticulum (ER) stress induced by the precarious conditions of the tumor microenvironment (TME). Furthermore, conditional deletion of the UPR-related PKR-like ER kinase (PERK) functionally reprogrammed tumor-MDSC into immune- stimulatory cells that partially restore protective anti-tumor immunity. In the related R01, we postulate that the accumulation of Bile Acids (BAs) in tumor-bearing hosts restricts the functional transformation of PERK-ablated MDSC. However, the validation of the BAs and ER stress axis in MDSC in human populations remains unknown. P2Et, a polyphenol-rich extract from plant Caesalpinia spinosa, promotes anti-tumor activities through activation of protective immunity and direct anti-tumor effects, both reducing the frequency of intratumor MDSC. Although P2Et induces anti-tumor actions in animal models, its effect in patient populations remains unknown. In this supplement, we aim to intersect a funded Phase I/II clinical study testing the effect of P2Et in Breast cancer (BC) patients receiving neoadjuvant chemotherapy in Colombia, South America, with R01-linked research testing the effects of MDSC undergoing elevated ER stress activation and alterations in plasma BAs. We hypothesize that patients receiving P2Et as part of their treatment regimen will show reduced numbers of ER-stressed MDSC and lower levels of circulating BAs, which associate with positive therapeutic responses. We propose the following Specific Aims: Aim 1. Evaluate the expansion of circulating MDSC and plasma BAs in stage II-III BC patients undergoing treatment with P2Et plus neoadjuvant therapy. Aim 2. Determine whether alterations in circulating MDSC and plasma BAs predict responses in stage II-III BC patients administered with P2Et. Proposed research will advance the scope of the parent RO1 by potentially elucidating the effects of the ER stress and BAs axis in MDSC from cancer patients...