BACKGROUND: Cancers are heterogeneous entities in which tumor cell populations as well as distinct host cell constituents form a dynamic and interactive tumor community that is pivotal not only for the genesis and progression of a tumor but also for the tumor's ability to resist therapeutic elimination. METHODS: We have been using a combination of genetic screening and coculture systems, as well as genetic and pharmacological approaches to functional elicit paracrine factors from tumor and immune cell compartments that convey GBM progression and resistance. RESULTS: We found that GBM tumor cells dependent on their subtype send out specific signals to immune cells that in turn respond by secreting prosurvival and proinvasive factors. Disrupting the communication between innate immune cells and tumor cells in mesenchymal GBM by targeting PI3Kgamma in immune cells blocked the communication to tumor cells, promoted polarization and antitumor activity and inhibited tumor invasion and growth and sensitized therapeutic approaches. CONCLUSIONS: Leveraging from these results, it is our intention to identify appropriate combinatorial treatment modalities that interfere with these compensatory feedback loops and help to develop an adequate polytherapy that is tailored to more successfully impede therapeutic resistance and prolong survival in the distinct GBM subtypes. SECONDARY CATEGORY: Preclinical Experimental Therapeutics.