GC has received grants, research support or is coinvestigator in clinical trials by Bristol-Myers-Squibb, Celgene, Boehringer Ingelheim, Roche, Tigen Pharma, Iovance and Kite. GC has received honoraria for consultations or presentations by Roche, Genentech, BMS, AstraZeneca, Sanofi-Aventis, Nextcure and GeneosTx. GC has patents in the domain of antibodies and vaccines targeting the tumor vasculature as well as technologies related to T-cell expansion and engineering for T-cell therapy. GC receives royalties from the University of Pennsylvania. FH reports grants from Prostate Cancer Foundation, Bristol-Myers-Squibb, Accuray Inc, Bioprotect, and non-financial support from Roche ImFlame cooperative group, European Organization for Research and Treatment of Cancer (EORTC) chairman Gynecology Cancer Group. FH has received honoraria for consultations from

SummaryAntiangiogenic drugs are used clinically for treatment of renal cell carcinoma (RCC) as a standard first-line treatment. Nevertheless, these agents primarily serve to stabilize disease, and resistance eventually develops concomitant with progression. Here, we implicate metabolic symbiosis between tumor cells distal and proximal to remaining vessels as a mechanism of resistance to antiangiogenic therapies in patient-derived RCC orthoxenograft (PDX) models and in clinical samples. This metabolic patterning is regulated by the mTOR pathway, and its inhibition effectively blocks metabolic symbiosis in PDX models. Clinically, patients treated with antiangiogenics consistently present with histologic signatures of metabolic symbiosis that are exacerbated in resistant tumors. Furthermore, the mTOR pathway is also associated in clinical samples, and its inhibition eliminates symbiotic patterning in patient samples. Overall, these data support a mechanism of resistance to antiangiogenics involving metabolic compartmentalization of tumor cells that can be inhibited by mTOR-targeted drugs.